2. COVID-19 Strategies and Future Scenarios

Key Messages

• The three possible future scenarios of Covid-19 are as follows (Fig 3). The containment of COVID-19 mentioned in the first scenario is impractical for most countries, and only a few exceptionally competent countries may stand a chance at it. Both scenario 2 and 3 indicate the long-term endemicity of the virus. The two are also similar in that they both aim for strength­ ened herd immunity, but the former entails the development of immunity during natural infec­ tion and the latter through vaccination. • Both scenario 2 and 3 call for “suppression” and “mitigation” to respond efficiently to the threat posed by the growing pandemic. The “suppression” approach - which centers around reducing the pace of spread and occurrence of new cases to minimize the number of deaths - imposes strict social distancing in addition to other common measures, including case detection, contact tracing, isolation, etc. On the contrary, one of the main objectives of the ‘mitigation’ approach focuses on coping with upheavals caused by COVID-19 to minimize the negative impact on the socio-economic sector rather than to reduce the number of deaths. The regulations associated with social distancing mostly apply to senior citizens over the age of 70 and other vulnerable groups (as seen in Table 2).

• During the past two to three weeks, we have seen countries of different income levels across the continents battling Covid-19 in their own ways. From developed countries like the US and Europe to developing countries like India have implemented strict measures, including the restriction of movement and comprehensive lockdown. This is in line with the ‘suppression’ policy aimed at curtailing mortality due to Covid-19 by subduing the spread of infection. • Known for its outstanding diagnostic capacity and well-executed social distancing practice that set an example for others, South Korea’s prospect for successful prevention of the spread of COVID-19 would depend on keeping a good balance between the two approaches, i.e., suppression and mitigation.

1. Opening words

2 April 2020

nd

The world has seen significant changes over the past two weeks as COVID-19 has continued to evolve. With New York, the heart of America, becoming the next Wuhan and the 1.3 billion population in India placed on quar­ antine, a total of 3 billion people throughout the world now have restricted freedom of movement. It is arguably ‘the greatest challenge since World War II’ ; the UK prime minister Boris Johnson has gone into self-isolation after testing positive for COVID-19, and the Tokyo Olympic Games, scheduled for July, has been cancelled.

The views and opinions expressed in article are those of the author and do not necessarily reflected the offi­ cial policy or position of Global Care. Correspondence to: Dr. Dong-il AHN, Glabal Care, Seoul, South Korea ahndongil@gmail.com

While Wuhan suffered greatly from the terror of COVID-19 since two months ago, countries that were slow to realize the severity of the situation -such as France, Germany, US, UK, Spain, India, and some African countries- were thrown into panic. The virus silently made its way into their lives, forcing their governments to enforce

1 In a televised address on March 18, German Chancellor Merkel asked her people to remain patient and cooperative, describing the fight against COVID-19 as the greatest challenge since WWII.

border closures to restrict the spread of the virus .

This report will look into strategic options that have been adopted on a global scale, as well as predictions on when and how COVID-19 may end.

2) Two necessary indicators for establishing COVID-19 strategies: Reproductive number and In­ fection fatality rate

The two major determinants to consider when establishing response policies and prevention measures upon outbreaks are ‘reproductive number’ and ‘in­ fection fatality rate.’ First, reproductive number means average number of secondary infection by a patient and it reflects the level of infectivity or transmissibility. Normally indicated as ‘R’ , a value higher than 1 denotes possible spread of the virus in its natural state with no public health measures applied. Nevertheless, improved personal hygiene, detection and isolation of patients, social distancing, etc., could bring it down to below one, which means the number of cases will decrease. Higher than 2, on the other hand, would contribute to an exponential increase in the number of cases during a generation population over a long period, forming a shallow curve. period . The other factor to consider is the infection fatality rate (i.e., IFR), which expresses the number of deaths out of total infected people as a percentage. Despite its pivotal role in determining the feasibility of prevention meas­ ures, however, the data available in most countries do not include unde­ tected cases. It is called the case fatality rate (CFR) rather than IFR; CFR indicates the number of deaths out of total detected and reported cases as a percentage.

Fig 1: The infection fatality rate and R value of various infectious diseases. The X axis represents the average number of people each patient may infect. The Y axis displays the fatality rate among the infected in percentage. (Source: New York Times, 18 Feb 2020)

As shown in figure 1, the R-value that remained below 1 limited the spread of MERS in its natural state. While the R-value of SARS was relatively high at 2.7, an organized effort towards prevention brought it down to under 1 and ulti­ mately contained the virus. In the case of the 2009 influenza pandemic with the R-value of 1.5, approximately 10 to 20% of the world population was estimated to have been infected. As for measles, a viral illness with airborne spread, the R-value stands at 15, making it highly contagious. Capable of asymptomatic spread, the R-value of Covid-19 is said to range from 2 to 4, which also places it in the category of highly infectious diseases.

The x-axis in figure 2 displays the number of days after initial infection and the y-axis shows the percentage of population infected. Whereas a high R-value, such as R=3.2 in the left, results in a substantial size of the population becom­ ing infected in a short period of time, a value as low as 1.1 only affects a small

Containment

Fig 2: Epidemic curves in accordance with the R-value The predicted figure shows the percentage of population infected depending on the R value (Source: CDC, US)

The y-axis in figure 1 shows the infection fatality rate. As obtaining precise results within the reported range of 0.1 - 3.0 requires verification of infection through antibody testing in blood samples, it is expected that this kind of data will be available from countries like China in the future. COVID-19 related fatalities which the media currently reports are CFR, with Germany, South Korea, Switzerland, US, and provinces in China other than Wuhan showing the lowest at 0.7 - 1.5%; and Italy, Spain, France and Iran showing relatively high figures from 6 to 11 as of March 2020. In South Ko­ rea and several Chinese provinces other than Wuhan where a large number of COVID-19 tests are performed, the low fatality rate appears to attribute to the presence of patients with mild symptoms, adequate treatment capacity, as well IFR, which cov­ as a slow increase in the number of confirmed cases or deaths. ers undetected or unreported cases in its denominator in these countries, will be lower than CFR, and the details of this will be addressed in the next report.

3) Response strategies: Containment vs Suppression vs Mitigation

The three public health policies or measures implemented in response to COV­ ID-19 are containment, mitigation and suppression. Even though the idea of suppression is not as widely emphasized as strategies of

containment and mitigation , as Professor Ferguson and team of Imperial College in UK have given it prominence as one of the key strategies to deal with the current pan­ demic, it is worth looking into in the COVID-19 context.

2 Most western democratic countries took measures similar to those adopted by the Chinese government. 3 The reproductive number is displayed as Ro at the initial stage and is gradually replaced by Rt over time. It is displayed as R in this article. 4 Generation period,” the period between the onset of symptoms of the initially infected patient and that of the next one, is said to be about four days. 5 Infection fatality rate = number of deaths / infections, Case fatality rate = number of deaths / confirmed cases. The gap between the two values diminishes when a large number of people are diagnosed, but becomes the opposite with a small number. 6 About 80% of all patients infected over a short period of time in the Daegu area turned out to have light symptoms as the diagnosis (of infection) took place only at certain locations, namely nursing homes and some religious groups. Furthermore, prompt action was taken to separate the severely infected from ones with light symptoms to avoid overburdening the health care system like Italy. 7 Whether Ferguson examined the idea of suppression in the same context as other cases from the past isn’t clear. Although he specified a drop in the number of cases as the R-value fell below 1, there was no mention as to how it distinguished from the containment.

While containment, by definition, refers to the status of keeping the outbreak high number of deaths is likely to happen due to rapidly increasing confirmed of a contagious illness under control through public health measures such as cases in a short period of time, which exceeds the health care system’s capacity isolation of patients and quarantine of the contact, it can also mean elimination to absorb as seen in Italy and Wuhan, China. The gray curve next to it displays of disease such as SARS in a broader sense. It is often referred to a policy or slower spread by means of protective measures, significantly decreasing the action taken prior to reaching the pandemic stage, which entails - contact trac­ number of daily cases and maintaining a manageable number of patients which ing, diagnosis and isolation, improvement of personal hygiene through frequent would lead to a decreased number of deaths. hand-washing, and social distancing - as a means to return to the pre-outbreak When an epidemic becomes a pandemic, stopping the spread of disease and state. lowering the R-level down to under 1 becomes incredibly difficult; detect­ The World Health Organization’s debate-inducing claim that containment is vi­ ing infection, isolation, and rigorous social distancing are a must. Efforts able at present stage is an important aspect to be considered, as its feasibility is to keep people in their homes and prevent them from traveling between regions anticipated through interim measures in some parts of the world. Since it may are seen as efficient means to control the quick spread of the virus leading to not be impossible for some countries (though most likely be very few) to reach serious infections. the containment stage at some point, the term ‘containment’ in this report is Mitigation used in the pandemic context.

Suppression

What the authorities often resort to when the suppression approach requires spending beyond their means or its restriction of personal freedom poses a so­ Once a pandemic is declared and public health measures in place fall short of cial threat to the economy, is mitigation. intended outcomes, the objectives are adjusted accordingly. The goal of sup­ pression, therefore, lies in flattening the curve to reduce the number of dai­ Choosing mitigation over suppression also implies an increased risk of the ly cases, in particular severe cases, and to lessen the burden on the health R-value exceeding 1. The spread of COVID-19 continues as the number of care system, which subsequently results in fewer deaths. Another goal is to confirmed cases rises in a short time, and more deaths occur as a result of insufficient treatment capacity. It would create a situation similar to that of bring down the reproductive number down to under 1. Wuhan where the fatality rate throughout the region once exceeded 20% before As seen in figure 3, each country or region has limited health care system ca­ it dropped to around 2 to 3% after the implementation of suppression policies pacity for treating patients. The steep pink curve in the graph indicates that a on 23 January (as seen in Fig. 4 and 5).

Fig 3: Flattening the curve. The X-axis shows the time since the first case and the y-axis shows the daily number of cases. (Source: CDC, US)

Covid-19 epidemics in Wuhan

No. of reported cases

Jan. 1 Jan. 10 Jan. 20

25 Reported deaths/Reported cases as of 20 Feb (CFR%)

1-10 Jan

Rt

Jan. 30

Feb. 9 Feb. 18

Onset date (2020)

Wuhan

Hubei (outside Wuhan)

China (outside Hubei)

China (overall)

11-10 Jan

21-31 Jan

1-10 Feb

11-20 Feb

Time Period 1 January to 20 February

Fig 4: Case fatality rate in Wuhan and the entire China (Source: WHO Mission report to China)

Jan. 1-10 Jan. 11-22 Jan. 23-Feb. 1 Feb. 2-18

Outbreak Period (2020)

Fig 5: Number of new cases (A) and reproductive number (B) in Wuhan, China. The R-value of 3.9 decreased after the implementation of mitigation measures. It was at 1.3 prior to lockdown, but 0.3 afterwards. (Source: British Medical Journal)

8 Of all COVID-19 patients, about 80% is considered to have light symptoms, 15% to require oxygen masks, and the remaining 5% to need ventilation treatment.

Another case in point would be measures taken during the 2009 influenza still considered to be inadequate as it is expected to exceed the treatment pandemic when the fatality rate was low. By being placed in the initial stage capacity in the UK by at least eight times. of the outbreak, the mitigation policy involving efficient diagnosis, firm quar­ antine regulations, closure of schools, and ban on congregations seems to have been an endeavor to diminish the risks through vaccination or herd immunity. To be discussed further is the type and extent of burden the aforemen­ tioned approaches impose on the health care system, as well as the poten­ tial number of patients each could bring.

Also known as “predictive modeling,” the next section will inquire into the roles of suppression and mitigation based on Imperial College London’s find­ ings.

4) Predictive Modeling by Imperial College London

As a government advisory group for COVID-19 and an active partner of the World Health Organization, Imperial College of London, along with Harvard Medical School and London School of Hygiene and Tropical Medicine, have been forerunners in epidemiological modeling. Imperial College London’s COVID-19 response team led by Neil Ferguson re­ leased a report around mid-March, with an emphasis on the possible negative outcomes of relaxed mitigation efforts and on appropriate measures for social distancing.

Although the findings drew the world’s attention by prompting the US and the UK to force their people into quarantine, the fact that they fit better in the Amer­ ican and British context makes it more advisable for countries like South Korea or China to focus on the applicable principles rather than the details. Reducing the number of contacts Shown in the table 1 below are possible public health interventions for reducing the number of contacts. Whether they fall under ‘suppression’ or ‘mitiga­ tion’ would be determined by the types of measures from a) to e) and the manner in which they are combined.

Types of Measures

Contents Closing all schools except for one fourth of universities

a. School Closures b. Self-Isolation at Home Self-isolation at home for symptomatic patients c. Voluntary Household Two weeks of isolation for families of patients Quarantine d. Social Distancing of Applicable to up to three-fourth of those aged > 70s 70 or older e. General Social Dis­ Aiming to reduce the average number of con­ tancing tacts by 25%

Table 1: Measures taken to bring down the number of contacts (Source: Corona report from Imperial College)

The Mitigation Model Figure 6 demonstrates the four types seen as appropriate for mitigation among the several measures (a-e) outlined and the expected number of hospital beds per 100 000 population needed to treat patients in critical condition. The first three measures involving “self-isolation at home” and “self-isolation at home + household quarantine for the families of patients + school closures” appear to be less effective in terms of decreasing the number of patients in critical con­ dition than when “self-isolation at home,” “self-isolation at home + household quarantine for the families of patients,” and social distancing for senior citizens over the age of 70 - are imposed simultaneously. This approach, however, is

The Suppression Model

Fig 6: Mitigation model. The Y-axis indicates the number of intensive care units per 100,000 population presumed to be necessary for different types of mitigation approaches. (Source: Corona report from Im­ perial College)

The predicted required number of Intensive Care Unit beds per 100,000 peo­ ple with the implementation of two suppression measures in table 1 is shown in figure 7 (A). 1) Household quarantine for the families of patients + social distancing for all citizens, 2) School closure + household quarantine for the families of patients + social distancing for all citizens; these two belong to the suppression category , as shown in the following: - Both suppression models are likely to be capable of maintaining a low fatality rate by accommodating all patients in need or exceeding no more than twice the capacity, as shown in the figure 7(B). - Social distancing between people would need to last for at least five months (for example, from 20 April to 20 September), and be reimposed in the event of a second wave, eventually leading to the demand of vaccines.

Fig 7: Suppression Model. The Y-axis indicates the number of intensive care units per 100,000 population presumed to be needed for suppression measures. Both measures seen in graph B are expected to be capable of accommodating all patients or to exceed the capacity by less than twice its maximum. (Source: Corona report from Imperial College)

Suppression

Mitigation

- Lower the R value to under 1, thereby slowing down the - Reduce the R value not necessarily lower than 1 which (slightly pace of spread significantly and reducing the number of decreases the pace of spread temporarily but) results in patients over time

Objectives

- Minimize the number of deaths by preventing

increased number of patients over time

- Easing overburdened healthcare system to lessen the number overburdened healthcare system (i.e., hospitalizations of deaths up to certain level (e.g., The UK is expected to see an in ICU)

Contents

Social Distancing - Applies to everyone regardless of age

Timeframe for - Needs to last for a minimum of 5 months (To be Social Distancing implemented on a need basis afterwards)

Table 2: Comparison of suppression and mitigation measures (Source: Corona report from Imperial College)

The Pros and Cons of Predictive Modeling by Imperial College London

- Fully implement and execute policies from table 1 simultaneously (figure 7)

- Only applies to those older than 70

- Several weeks or slightly longer

increase of 8 times the treatment capacity)

- Partially implement and execute policies from table 1 (Figure 6)

Scenario 1: The containment of COVID-19 within several months It seems inevitable that such epidemiological studies have a significant impact Most experts have come to the conclusion that complete containment of Cov­ on the decisions of policy makers around the world. While many governments id-19 is almost impossible once it reaches the pandemic stage. Even if some including the US, UK, Spain, France, Germany, India, and Malaysia have been country like China successfully contained COVID-19, the positive out­ enforcing suppression or mitigation policies, their focus would need to be comes would be short-lived due to infections among those returning or vis­ on assessing the practicality and efficiency of the measures on their own iting from abroad. Enduring the economic crisis and social costs brought on terms, and adjusting them to meet the public’s needs in various sociocul­ by the pandemic while enforcing isolation and distancing regulations in a glo­ tural circumstances rather than (implementing) the measures per se. balized, interconnected world for longer than a certain time period has turned out to be incredibly challenging for most countries. As of 29 March, China has This model was meant to be more efficient when implemented in Europe or not detected a new local case, but a few cases from abroad were identified since the US than other parts of world including China or South Korea. In the case their last confirmed cases on 19 March. More observation would be needed to of Imperial College London’s findings, intensive case findings were excluded determine China’s prospects in the long-term. from both the suppression and mitigation measures. The emphasis appears to have been on predicting the effects of varying degrees of social distancing on Having managed to reduce the occurrence of new cases successfully, South case reduction rather than intensive diagnosis due to limited diagnostic capacity Korea soon has to decide on the most viable course of action among what’s in the US and the UK.

available. Another difficult choice to make when faced with either scenario 2 or 3 would be whether to utilize suppression or mitigation (e.g., extended In the case of Wuhan, public health agents conducted a thorough screening, school closures vs re-opening of schools). The situation in China may have going from door to door in an effort to find those potentially infected for further referential value for further planning and decisions. testing and place them under isolation or quarantine if necessary. The same was done in South Korea. The competent handling of the virus by both coun­ Scenario 2: An increasing number of people develop immunity through tries seems to ascribe to their constant effort towards early detection along with natural infection, and the virus appears intermittently on a seasonal basis abundant treatment capacity. Ferguson’s modeling, therefore, would not be ide­ (i.e., endemic) al for South Korea or China. The reason this scenario seems most likely to occur along with scenario 3 is Table 2 is a summary of suppression and mitigation.

5) Future scenarios

Finding answers to how the pandemic will play out over the coming years and eventually end, requires information such as the number and infectivity of asymptomatic individuals, the number of confirmed cases (in order to attain IFR), the probability of mutation, the timeframe for vaccines and their efficacy, the presence of immunity after infection, the effects of weather on COVID-19, etc. With limited information at this stage (and at the time of this report), the following three scenarios can be outlined: Scenario 1 : The containment of COVID-19 within several months Scenario 2 : Constant spread of virus and development of herd immunity, followed by endemic status with intermittent or seasonal outbreaks Scenario 3 : Development of immunity through vaccinations, followed by endemic status with intermittent or seasonal outbreaks

due to past incidents. Figure 8 shows how three influenza pandemics became

Fig 8: The three influenza pandemics that occurred in the US and the percentage of deaths among those aged older than 65 over time (x- axis displays year and y-axis indicates the excess death among persons over 65 years implying death due to influenza)

9 Though the US has recently strengthened its capacity to diagnose, it was very limited in early to mid of March when the Imperial College London’s findings were reported. 10 On March 22, Myung Don Oh, the head of central clinical committee for emerging disease control in South Korea gave positive remarks about south Korea’s unprecedented effort to combat COVID-19, along with limitations observed in some of the approaches. One of his concerns being the potential increase in the number of cases upon the start of school, he highlighted the need to determine the type of measures to enforce or ease based on consensus of society and its members. 11 There has been a total of four pandemics including the 2009 influenza in the past century alone.

endemic. The Spanish Flu (H1N1) dating back to 1918 took the lives of more Similar to the second scenario in some ways, the key difference lies in the de­ than 40 million people during the 18-month period, and showed up intermittent­ velopment of immunity through vaccination rather than natural infection. The ly over the following forty years. It only disappeared when the Asian Influenza required timeframe, cost, amount and more importantly the safety and efficacy A (H2N2) pandemic made its appearance in 1957, which was also replaced by of the vaccine would be essential. Despite 1 to 1.5 years being the usual time frame for creating a vaccine, the one developed for the 2009 Influenza was Hong Kong Influenza pandemic in 1968-1969 after ten years. mass produced within half a year. Scenario 3. The spread continues until vaccines are completed, herd im­ munity is achieved through vaccination and the virus appears intermit­ Table 3 below displays various measures for different prospects. They may or tently on a seasonal basis (i.e., endemic). may not work depending on the circumstances.

Scenario

Contents

Possibility

Examples

Measures to be taken/Notes The spread comes Containment at the pandemic a) SARS: Broke out in No­ In case of China, political and fiscal to a halt and no stage is said to be impractical. vember 2002 and contin­ burdens of regulating measures in­ new cases occur.

ued its spread across 26 volving social distancing, isolations As an exception, China may countries, but was finally and lockdowns may require shifting The virus is consid­ reach this stage. However, it eliminated in May 2004. to scenario 2 or 3. ered to have been would not last long and very 1. Contain­ contained when no likely 2nd and 3rd waves will b) Ebola: Emerged peri­ new cases are re­ occur as new cases may be im­ odically in Africa since its ment ported during twice ported from abroad. the typical incuba­ tion period (14 x 2 In China, if difficult to contain = 28 days in case of COVID-19 across the entire COVID-19).

initial outbreak in 1976.

country, may shift its focus to certain areas like Beijing. A herd immunity Scenario 2 is expected to be Resembles infectious dis­ Each country is to choose between established if 50- put in place in the case of de­ eases prior to the modern suppression and mitigation as men­ 2. Prolonged 60% of population lay of vaccine development in era when there were no tioned before. vaccines or treatments. spread + infected, then scenario 3. Many low-income countries may herd immu­ settles into a sea­ nity through sonal pattern and A hybrid of scenario 2 and 3 An estimated 40 to 50 need assistance on a global level to natural become endemic. is presumed to take place de­ million people were as­ achieve herd immunity through vac­ pending on the release period sumed to be dead due to cination once it is developed. Other­ infection+ for the vaccine. endemicity

the Spanish Flu in 1918, wise these countries would remain prior to achieving herd in scenario 2 instead of shifting to immunity.

scenario 3. Prolonged pan­ Usual leading time for vaccine Vaccines for the 2009 in­ Each country is to choose between demic comes to development is around 1-1.5 fluenza (H1N1) that broke suppression and mitigation as men­ halt with the help years. 3. Prolonged of mass-produced

out in April 2009 were ful­ tioned before. ly developed and distrib­ spread+ herd vaccines. The The escalating race for a vac­ uted in September of the 50 million vaccines secured from pharmaceutical companies by the immunity spread stops, set­ cine is presumed to enable its same year. World Health Organization were through tles into a seasonal completion before the end of successfully distributed to expect­ vaccination + pattern and be­ this year at the earliest. ant mothers and vulnerable patients endemicity come endemic. with underlying conditions in devel­ oping countries in H5N1 influenza pandemic in 2009.

Table 3. The outcomes of each scenario in the past and related policies (Source: Adjusted based on article from Vox)

12 The infection of roughly 50% to 70% of the entire population is known to achieve herd immunity, provided the R-value equals 2.5. The number of people needed to gain herd immunity through infection corresponds to the R-value.

6) Concluding Remarks

This volume has scrutinized ways in which Europe and North America, after COVID-19 spread from Asia, are tackling the pandemic situation, including the measures taken under different circumstances, barriers to be avoided and intended outcomes, followed by a number of scenarios suggesting great challenges in 2020. As the majority of predictions regarding the new life-changing virus in this report rely on limited findings and results, the anticipated number of related deaths is excluded despite its availability; it will be mentioned briefly in the end of the special report series.

Humanity is at a point where learning from the past is more necessary than ever to overcome current challenges. The topic to be covered in the next report is the history of virus pandemics over the past century and how they have been handled .

Acknowledgements

We thank Mhin-jine KIM, MHS Univ. of Illinois at Chicago, Division of Health Policy and Administration, for translation review.

13 H1N1 influenza pandemic in 2009 and Spanish flu in

References

Articles • Adam Kucharski,etc, Early dynamics of transmission and control of COIVD 19: a mathematical modeling study, Lancet, 11 Mar 2020 • CDC, Community strategy for pandemic influenza mitigation in US, Feb 2007 • Editorial, Coronavirus response: a focus on containment is still apt, Nature, 3 Mar 2020 • Chen Shen, etc Review of Ferguson, et al, ‘Non-pharmaceutical interventions…’, New England Complex Systems institute, 17 Mar 2020 • Chaolong Wang, etc Evolving epidemiology and impact of non-pharmaceutical interventions on the outbreak of corona virus disease 2019 in Wuhan China, medRxiv (not peer reviewed) 3 Mar 2020 • Imperial College COVID 19 Response Team, Impact of non-pharmaceutical interventions to reduce COVID 19 mortality and health care demand, Imperial College London, 16 Mar 2020 • L. Villant, Epidemiology of fatal cases associated with pandemic H1N1 influenza 2009, Euro-surveillance, 20 Aug 2009 • World Health Organization, Report of the WHO-China joint mission on coronavirus disease 2019, 16-24 Feb, 2020

Media • David Adam, Modelers struggle to predict the future of corona 19 pandemic, Scientist, 12 Mar 2020 • Nick Paton Walsh, US, UK coronavirus strategies shifted following UK epidemiologist’s ominous report. CNN, 17 Mar 2020 • The learning network. How does the new coronavirus compare to other infectious diseases. New York Times, 2020.2.18 (https://www. nytimes.com/2020/02/18/learning/whats-going-on-in-this-graph-coronavirus-outbreak.html)

• 임준호, 코로나 19 정책 한계, 개학 후 환자 증가 가능성, 톱스타뉴스, 2020.3.23

The global community has been hit with unprece- dented panic as COVID-19, a new infectious disease spread at an alarming rate and spread to the African continent in just a month through Europe as well as Asia. WHO declared an international public health emergency due to the COVID-19 situation, and they

situation on March 11. Global Care, an international health and medical NGO that has been working on health care projects in various countries in Asia and Africa for the past two decades, has planned to issue special report to discuss the worldwide COVID-19 situation and to share its future prospects and consider what to do in the era of globalized infectious diseases.

4. What Happens After the First Curve?

• The weeks-long lockdown that took place in Europe since March seemed to be effective in containing the spread of COVID-19, to see an upward trend since the lockdown was released. The spread of the infection continues across North and South America as well as Asia, where the effect of the lockdown is unclear. Although the number of new COVID-19 patients in Africa is decreasing after reaching its peak, it is also noted that it may be an illusion due to the lack of diagnostic capacity (see Figure 1). • There is an exciting prospect of developing the COVID-19 vaccine by early next year or in the middle of next year. Currently, individual efforts between countries to secure COVID-19 vaccine and international cooperation (e.g., Covax facility) coexist.

• Currently, the epidemiological aspects of COVID-19 in major countries around the world can be divided into four groups (see Figures 3, 4 and Table 2): Persistent (Group 1), Single Curve (Group 2), Two Curves (Group 3) and Hybrid (Group 4). Korea has recently changed from Group 2 to Group 3. • When predicting different scenarios for epidemiological evolvement of COVID-19, the most than two or three multi-curves (see Figure 8). • University of Minnesota’s Infectious Diseases Research Policy Center presented three COV- ID-19 epidemiological scenarios that will help predict the development of COVID-19 curves by the end of 2021 (see Figure 9).

1. Opening words

1 Sep 2020

st

Weeks have passed since the third special article was published. As the situation around the world is constantly changing, and COVID-19 crisis has become more like a (long term) marathon than a sprint, the 4th article was published slightly later than originally planned. Special reports have been issued since middle of March, and you can download previous reports in European countries entered a tentative period of stabilization as the number of patients decreased due to the Global Care website. (http://www.globalcare.or.kr/) , sec- ond curves began to form as the number of patients increased again as the lockdown was released and summer The views and opinions expressed in article are those - vacation season started. Concerns are mounting in South Korea as the recent number of patients continues to cial policy or position of Global Care. become the main content of this article. Correspondence to: Dr. Dong-il AHN, Glabal Care, Seoul, South Korea ahndongil@gmail.com

2. Situation updates on COVID-19

The biggest changes related to the global COVID-19 situation and its response between May 10 (when the 3 article was published) and early September will be discussed with a focus on the following three points

rd

1) Epidemiological situation after release of lockdown

Third , there are cases of developing countries in Asia and in Africa. In Asia, the number of patients continues to increase in many countries, including In­ dia, Indonesia, and the Philippines. Although these countries also implement­ ed lockdown policies, it was questionable whether the lockdown would be

Lockdowns and social distancing policies that have been in place for weeks or more since March or April in developed countries as well as in many developing countries have been partially or substantially lifted since June. The effective from the beginning due to problems of livelihood and food shortages following three aspects have been observed (see Figures 1,3,4 and Table 2). that could easily be worsened due to the lockdown. This seems to be the case in which such concerns have become a reality. On the other hand, Africa’s First , the number of new cases, which had continued to increase in several daily number of patients across the region has been on the decline since its countries, including Western Europe, peaked and then declined from June peak in July, and the number of infections per million population is reported to July, which can be seen as an impact of COVID-19 induced lockdown. to be much lower than other parts of the world. Despite Africa’s environment However, with the lockdown being lifted and social distancing being eased that makes it difficult to expect the effects of lockdown policies as it was the during the summer vacation season, the number of new patients has gradually case in developing countries in Asia, the number of patients reported so far increased in recent weeks, showing instability. Some countries like Spain seems to be relatively well defended in this war against COVID-19. However, and France have developed second curves with a significant increase in the there are many perspectives/viewpoints that this could be due to significant­ number of new patients. ly low COVID-19 diagnostic capacity and limited patient information and reporting system, which could lead to much underdiagnosed or underreported Second , there are countries like the United States (U.S.) and many Latin number of patients compared with other continents. Thus, it requires careful American countries such as Brazil, Peru, and etc. that show little to no lock­ interpretation. Moreover, Africa has a lower mortality rate than other conti­ down effect and continuous increase in the number of patients. It seems that nents. This can be seen as the result of various factors, such as demographic the government’s enforcement of the lockdown was quite weak; there were characteristics of low percentage of elderly population, which is the age group uncertain policies on strengthening personal hygiene such as wearing of masks known to be most vulnerable to COVID-19, and lack of postmortem diagnosis or lack of cooperation among citizens on national policies contributed to such of COVID-19. limited effect of lockdown.

Situation by WHO Regions

Figure 1: Daily trends for new patients by region. The Americas refers to the combination of North and South America, with the number of patients in the U.S., Brazil, Peru, and Mexico increasing steadily. Europe has shown a decline since the first curve but the patient numbers have gradually risen. A clear second curve has formed in Spain and some European countries. South East Asia continues to have first curves spread by India, Indonesia, and Bangladesh. The African region has passed the peak of the first curve and continues its gentle downward trend. (Source: WHO, 1 Sep 2020)

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1 Estimating the number of infected patients based on antibody test rates in Africa sometimes shows that the estimated number of patients can be hundreds of times higher than the actual number of patients diagnosed and reported, raising suspicions that the proportion of undiscovered patients is incomparably higher than that of Europe and elsewhere. For example, in Kenya with a population of 51 million, a COVID-19 antibody test in June showed that 5.6% of the population was infected. That means there are about 2.86 million patients, with only 3,700 reported by mid-June. This means there could be approximately 770 times more patients than reported (2.86 million/3700=770). In Europe, the difference is estimated to be only about 10 times. In addition to the absence or lack of diagnostic capabilities in Africa, there are claims that positive COVID-19 antibody tests could occur if infected with other diseases such as malaria. However, no medical grounds have been provided to support them. 2 For demographic characteristics, please refer to page 4-5 of the third periodical.

2) Antibody test results indicating the degree of spread of COVID-19 infection and infection fatality rate (IFR)

In addition, the infection mortality rate in Spain is calculated as follows. The cumulative death toll from COVID-19 until early May was about 25,000 people. When the number is divided by the cumulative number of patients found by early May (254,000), a high mortality rate of 9.8% is

Since the beginning of the COVID19 pandemic, most developed countries as well as developing countries have not been able to perform sufficient tests due to their considerable lack of diagnostic capabilities. Therefore, it is known that there is a significant difference between the reported number of patients with COVID-19 and the actual number of infections from each country. Thus, antibody tests can be conduct­ ed to estimate the extent of exposure (i.e., infection) to COVID-19 to determine i) what percentage of calculated. However, when divided by 2.35 mil­ the population has been infected so far, and ii) infection fatality rate, which can be used to establish lion infected people, a much lower death rate of future COVID-19 policies. Antibody tests were conducted in several countries between April and June, around 1.1% is shown (25,000/2.35 millionx100 = 1.1%). and the some of distinguished research findings are shown in Table 1.

Table 1. COVID-19 Antibody Test Results by Country. Country/ Region positive rate Antibody Time of test

Spain

5%

Sweden/ Stockholm

7.3%

6.3% (London 17%) End of May thickly) populated. The research is still being conducted

England

Wuhan China/

3.5%

20% (State of New York: 15%) End of May

USA/ New York

Italy/ Bergamo

57%

Japan/ Tokyo

Beginning of June

1%

Korea (all areas except

0.03%

Daegu)

Source: Lancet, British Government, New York City, etc.

Detail End of April to Mid-May National level studies have been published in medical journals, and they are one of the most cited studies. A study drew much attention because it was an important indicator regarding the formation (and success) of herd 2020. In the case of Stockholm, Sweden, which End of April immunity.

London was found to have higher antibody positive rate than the national average, as it is more densely (and and its final results will be released in the future. Beginning It is the world’s first antibody test, which was conducted at a time when it was estimated to have most antibody of March to formation after the lockdown was imposed. However, the beginning of April positive rate was lower than expected.

The actual positive rate is estimated to be lower as the sample was biased with many volunteers wanting anti­ body tests participated in research. End of April (Unusually) High rate reflects the unique situation in northern Italy, where the largest number of COVID-19 to beginning of June patients in the world have occurred collectively.

A relatively low positive rate was reported compared with other studies. However, only about one-third of infected the infection fatality rate of COVID-19 is not patients were identified and reported. Excluding Daegu, which has the largest number of patients, antibody positive rate was very low. One study, which was conducted in university hospital setting and focused on the Daegu region, showed very high positive Mid-April to mid-June results. To obtain more accurate information, the Korea Centers for Disease Control and Prevention (KCDC) is currently conducting a nationwide antibody positive rate investigation.

As shown in Table 1, the antibody positive rate can be as high as 57% as seen in the Bergamo region, which turned northern Italy into the city of fear and death, and it can be less than 0.1% as seen in South Korea, where patient detection and contract tracing were most closely managed in the world. In general, the antibody positive rate is estimated to be around 5% worldwide as of May is implementing a herd immunity policy, the an­ tibody positive rate is about 7% , which is lower than expected so some people predict it will take substantial time until herd immunity is formed by natural infection. However, some believe that the spread could be delayed even when the commu­ nity infection rate reaches around 40 percent, so there is a need to wait and see.

Many epidemiologists believe that the global infection fatality rate (mortality rate versus the number of infections), which is the most important indicator related to death, is in the range of approximately 0.3%-1.0%. It is true that this is a big difference compared to the patient mortality rate (mortality rate to the number of cases discovered), which is known to be around 3-4% worldwide. Compared with the infection fatality rate of seasonal influenza, which is known to be about 0.1%, some say significantly high. However, as COVID-19 is a novel infectious disease that has appeared in humans and can continue to spread until 60-70% of humans are infected, it can be seen as being unmatched by seasonal influenza (which has lim­ ited spread of infection due to significant devel­ opment of immunity over a long period of time). COVID-19 is expected to co-exist with humans for a considerable period of time (probably until a new pandemic virus emerges). However, due to the spread of infection, development and inocu­ lation of vaccines, etc., incidence and mortality of COVID-19 is predicted to be significantly reduced after the first 2-3 years have passed.

The degree of infection and the infection fatality (or mortality) rate through antibody tests can be seen as the following example of Spain. Spain has a population of approximately 47 million and an antibody positive rate of 5%. Therefore, about 2.35 million people (47 million x 5 percent = 2.35 million) have been Antibody positive rate is an important data for estimated to be infected. By early May, when the test was conducted, the cumulative number of COVID-19 COVID-19 policy decisions. Therefore, WHO is cooperatively supporting many countries in patients found after the test in Spain was about 254,000. In other words, only about 10.8% of all infected conducting antibody testing according to the patients seemed to have been found (254,000/2.35 million x 100 = 10.8%) because a) in many cases, the international standards under the name of “Soli­ symptoms were mild and patients did not consider having contracted the disease (in fact, about 80% of darity 2” project. COVID-19 patients was known to be mild) or b) the diagnostic test was not conducted. The same calcula­ tion in the U.K. and China’s Wuhan region, as in Spain, shows that there is a difference of about 10 times or more between the estimated number of patients infected and the number actually reported.

3 The infection fatality rate is a percentage of deaths among all infected people, and the number of patients suspected to have been infected can be obtained by conducting antibody tests. For more information, see the page 2 of the second periodical. 4 In a media interview on August 9, Anders Tegnell, who is the head of the Swedish government’s epidemiological team and has led the herd immunity policy, said he believed about 30 percent of Swedish citizens were infected at the time, hinting that he was not giving up hope for herd immunity. 7.3% of Table 1 is the result of tests conducted at the end of April (which therefore reflects the antibody positive rate about two weeks ago, about mid-April), and then the test conducted in June showed a10% positive rate.

3) Advances in vaccine development As the lockdown was released and COVID-19 infection, which had subsided for some time, entered an upward trend, vaccine has emerged as the only hope. Let us briefly go over the issues related to when an effective and safe vaccine will become available, procurement of vaccine, and vaccination.

A. Timeline for Vaccine Development • Usually, vaccine development takes many years. However, it is predicted that the time needed for development will be greatly reduced as the development risk has dropped due to massive financial support from the U.S., Europe, and China, and vaccine development technology has improved. Figure 2 shows the status of vaccine development as of August 25, 2020. More than 170 vaccine development projects are un­ derway worldwide, with seven cases reaching the most important and time-consuming final (third) phase of clinical trials. Out of these sev­ en pharmaceutical companies, China has the most with four companies and U.S., Britain and Germany each has one company. These pharma­ ceutical companies have generally set a timetable of 12-18 months, and have begun research/development since early this year. Many experts predict that large doses of vaccines will be available (early next year or) in the middle of next year. Once the vaccine is developed, it is com­ mon for it to go through the approval process of the U.S. or European Food and Drug Administration (FDA) and then to domestic and overseas sales. Under the special circumstances of COVID-19, some countries are accelerating their vaccine approval and inoculation without following the global standards.

Figure 2: The stages of vaccine development and the number of participating pharmaceutical companies. The top represents the pre-clinical stage of the trial to FDA approval through phase 1,2,3 of the clinical trial, with seven pharmaceutical companies currently conducting phase 3 trials (Source: WHO/Washing­ ton Post, 25 Aug 2020)

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B. Securing vaccine • Securing vaccines is as sensitive and politically important as securing nuclear weapons or new advanced (high-tech) weapons during a war situation. Many countries including U.S. and some European countries have been investing huge amounts of dollars early on to secure vaccines

be left to free market like general goods. Moreover, COVAX Facility, an international initiative, was recently established to ensure fair access to vaccines for many countries, including developing countries. It aims to act as a catalyst for vaccine development, increase vaccine production capacity and adjust for fair distribution. Currently, 75 countries have joined COVAX with the goal of securing 2 billion doses of vaccines by 2021 and distributing them equally. • Even if multinational pharmaceutical companies develop vaccines, their production capacity falls far short of the huge demand. Therefore, they should ask several other pharmaceutical companies for consignment production to improve their supply capacity. Korea is planning on partic­ ipating in the production of vaccines as it is recognized for its techno­ logical prowess in consignment production, and the scale of production is not small. In this case, Korea is expected to secure a certain amount of vaccines produced.

C. Vaccination • The vaccine is expected to be approved by the U.S. Food and Drug Administration (FDA) if phase 3 clinical trials prove that at least 50% immune response is formed after vaccination. Governmental policies on vaccination will depend on: 1) how effective the newly developed vaccine will be, 2) how long the period of immunity will last, 3) and whether the elderly population, the high risk group for death from COVID-19, will have as much protection effect from the vaccine as the younger age group (the clinical trials of the vaccine usually involve participants of young age who have good immune response). Moreover, there is a need to examine whether there is substantial variation occurring in the same type of virus used in vaccine develop­ ment during the subsequent spread of infection, and if so, how much is vaccine efficacy reduced due to such phenomenon. If so, there is a need to examine how much reduction in the effectiveness of the vaccine occurs. The allocation of a limited amount of vaccine is also a sensitive issue, and should be determined by each country considering various issues such as occupational type, health condition, age, etc. In the case of the 2009 H1N1 pandemic influenza, the WHO recommended that health care personnel, patients with chronic diseases and pregnant mothers be vaccinated first. • The point in which herd immunity is formed due to the spread of COVID-19 natural infections or increased vaccination will also be an important indicator of vaccination and COVID-19 policymaking.

3. What happens after the first curve?

1. Changes in epidemiological curves in major countries Figure 3 shows the trends of daily new cases in the so-called Top 12 countries with the highest cumulative number of patients. Figure 4 shows the trends of daily new cases in major countries with relatively good diagnostic capabili­ under research and development by pharmaceutical companies based on ties. Table 2 refers to the analysis of the epidemiological patterns of major free market logic. countries in Figures 3 and 4 divided into four types. • On the other hand, vaccines are global public goods, so they should not

5 The shortest case was the development of a vaccine for mumps known as spectacle, which took four years, followed by polio vaccine of seven years, measles vaccine of nine years, and phospholipid virus vaccine of 15 years. 6 AstraZeneca (U.K.) and Moderna (U.S.) are known to be at the forefront of vaccine development, while there are BioNTech (Germany) and China’s four pharmaceutical companies (CanSino Biological Institute, Sinovac, Wuhan Institute of Biological Products, and Beijing Institute of Biologics). Including Russia’s Gamaleya Research Institute, which reported it will start vaccination since August when clinical trials were not complete, a total of 8 pharmaceutical companies are currently conducting phase 3 clinical trials. 7 The newly developed vaccine usually needs to prove at least 50% efficacy to be approved by the U.S. FDA. The standard procedure regarding new drugs or vaccines is importing products approved by the U.S. or European FDA and registering them in one’s own country. China’s State Council recently approved the emergency use of its own vaccine, which has not been completed clinical trials in June, and has already been using the COVID-19 vaccine for certain population groups, including soldiers, since July, according to media reports. Russia has also announced that it will begin using the vaccine in clinical trials in August. On August 31, the U.S. FDA Director also mentioned that the use of vaccines may be approved for emergency use by certain groups, even before clinical trials of the vaccine are completed. 8 COVAX was recently established by the Gavi (Global Alliance of Vaccine Initiative), WHO, and CEPI (Cooperation for Epidemic Preparedness Initiative). 9 COVAX puts forward the principle that when a vaccine is developed, 20% of each country’s population should jointly purchase the vaccine and supply it at a reasonable price. COVAX currently has nine vaccine candidates through the Coalition for Epidemic Preparedness Innovations (CEPI), eight of which have entered clinical trials, including the vaccines of Moderna and AstraZeneca, which have entered phase three. 10 South Korea’s SK Bioscience signed a consignment production contract with AstraZeneca of UK in July and NovaBax of US in August for the COVID-19 vaccine. 11 Moderna recently conducted a separate clinical trial to prove its vaccine efficacy on elderly population. After injecting the two doses of vaccine in a 28-day interval, Moderna announced that it resulted in the forma­ tion of heavy chemicals that neutralized the virus and T cells which play an important role in the human immunization system. 12 The problem of reduced vaccine efficacy due to mutations in viruses is often observed in influenza or flu. However, as less mutation occurs in COVID-19 compared with the influenza virus, it is predicted that there will be a less problem of reduced vaccine efficacy due to mutation. 13 In the case of significant decrease in diagnostic capacity, the numbers were excluded from the analysis because the difference between the reported number of patients and the actual number of infected patients was too great to be reliable.

Figure 3: Trend of daily patients in Top12 countries – see group 1-4 in Table 2 (Source: WHO, 1 Sep 2020).

Group 1 (Persistent)

Group 2 (Single Curve)

Group 3 (Two Curves)

Group 4 (Other/Hybrid)

Figure 4: The daily trend of new patients in other countries – see group 1-4 of [Table 2]. (Source: Worldometer, 1 Sep 2020)

st

Indonesia

New Zealand

France

Turkey

st

China

South Korea

Sweden

Table 2. COVID-19 epidemiological patterns in major countries around the world. (Source: author’s writing based on Worldometer data, 1 Sep 2020)

Example Epidemiological pattern (Top 12 countries)

U.S.A, Brazil, India, Peru, spread without forming a Mexico, Columbia, Iran, Argentina clear first curve.

Infections continue to Group 1 (Persistent)

Group 2 (Single curve): After the formation of the South Africa, Chile first curve, incidence rate of new cases remains low or somewhat stable.

st

Example (Other countries)

Indonesia

• Currently, the incidence rates of China, New Zealand and Taiwan China, New Zealand, Taiwan, are quite low. Thailand, Saudi Arabia, • Chile has about 2,000 new cases per day, but the overall trend is Pakistan close to Group 2.

Note

• The number of cases in the U.S. and Peru rose again before a distinct first curve is formed. Therefore, they have been classified as group 1, not group 3. • Iran is classified as group 1 instead of group 3 because the reduction of cases in the end of April was not clear.

After the first curve, the Group 3 (Two curves)

Spain

second curve is currently in progress.

Group with hybrid curves Group 4 (Other/hybrid)

Russia, Italy

2. The “Spanish” Influenza Pandemic

• Korea belonged to Group 2, but unfortunately it was recently France, Vietnam, Japan, Australia, changed to Group 3. However, Korea’s first and second curves are Morocco, South Korea

Sweden, Turkey

The first group includes several Top 12 countries, including the U.S., Brazil and India. The absence of national leadership, policy confusion leading to ineffectiveness of lockdown policy, and the failure to form national solidarity have caused the number of patients to continuously increase since March without a clear peak point.

The second group continued to decline after the first curve peaked, and the formation of the second curve has yet to take place, with the incidence of new patients remaining low or showing a relatively stable pattern. They are among the most prominent winners in the current war against COVID-19. China , New Zealand, Taiwan and South Africa, along with Thailand are part of this group. National leadership, strong lockdown policies and travel restrictions for reviving the economy are seen to be major reasons. Korea belonged to the group until early or mid-August, but recently moved into the third group.

The third group had a first curve formed due to lockdown policy, but a s econd curve was formed due to lift of lockdown, hasty economic revival policies overlapping with summer vacation season. Spain was the first European country to form a second curve, and France, Japan, and South Korea joined this group. These are countries considering policy options between strengthening and easing social distancing (or deciding whether to reimplement lockdown policies or not).

The fourth group shows various forms as other groups, often in the hybrid form of groups 1, 2 and 3. Over time, some countries may be transformed to groups 2 or 3.

As shown above, the epidemiological situation proceeds with showing these different patterns. The chang­ es in epidemiological dynamics are likely to be determined by 1) the presence and degree of variation in the virus, 2) changes in human behavior patterns (e.g., washing hands and wearing masks, personal hygiene, social distancing, patient isolation and quarantine, etc.), and 3) environmental factors (e.g., popu­ lation density, climate, etc.).

A. The situation and consequences of the 1918 influenza pandemic • As Table 2 shows, predicting what kind of epidemiological curve COVID-19 will portray over the next 1-2 years will be helpful and interesting for policymaking as well as informative for many peo­ ple who are going through their daily lives with COVID-19. For this very reason, many scholars are traveling back to 100 years ago for the following reasons. • In addition to COVID-19, SARS and MERS are also caused by viruses belonging to the COVID fam­ ily. In both cases of SARS and MERS, it disappeared after a few months before becoming a pan­ demic (in the case of SARS), or caused intermittent and sporadic spread in some restricted areas (in the case of MERS). Therefore, they cannot be compared with COVID-19 in terms of epidemiological characteristics. COVID-19 is instead shown to have more similar epidemiological characteristics of the 1918 influenza pandemic.

much lower than those of Spain and France, which do not differ much in terms of population size.

• Russia is currently experiencing downtrend after it passed the peak of the first curve. • Italy is in the early stage of second curve formation, between groups 2 and 3. • Turkey is close to Group 2. However, the incidence rate of new cases is maintained at a high rate

• Prior to COVID-19, there were about four influenza pandemics over the past century. One common feature of the influenza virus and the COVID-19 virus which both caused pandemics is that they are basically diseases that cause respiratory infections, and there are various patients from asymptomatic patients to critical patients who may face death. Moreover, because they are infected through contact, nasal mucus and aerosols, personal hygiene practices (e.g., hand wash­ ing and wearing masks) are important for COVID-19 prevention. The important dif­ ference is that although both asymptomatic patients of the influenza pandemic and COVID-19 develop infections, there is a higher proportion of asymptomatic patients in COVID-19 patients, and a longer incu­ bation period of COVID-19 than influenza pandemic (because more infections from asymptomatic patients occur during the in­ cubation period). Therefore, it is known that COVID-19 propagation or transmission is higher. In fact, the initial R0 value of COV­ ID-19 is 2-2.5, higher than the R value of influenza pandemic (i.e, 1.5-1.8). • Out of the four influenza pandemics in the last century, the Spanish flu of 1918 is the most suitable example for comparison to COVID-19 in terms of its magnitude of the spread of infection or the extent of death.

14 For example, in Brazil, President Bolsonaro said, “People die someday. If this situation continues, serious levels of mass unemployment will occur, which will take years to recover. You cannot stop the car factory because of a traffic accident.” Brazil currently has the second largest number of new patients with COVID-19 in the world after the U.S. 15 China had a temporary increase in the number of patients in the Beijing area in June after the first curve, which had peaked in Wuhan in January and February, completely subsided. However, only a few new cases of COVID-19 have been reported since then. Most of the new patients are from overseas. Currently, it is reported that it is hard to see people wearing masks in Wuhan, and that residents’ lives have completely returned to daily life. 16 All viruses always mutate without any exception. After mutation occurred in the COVID-19 virus and transferred to Italy from Wuhan, it spread across the world (the mutated virus is known to be ‘D614G’ type.) Currently, D614G is the major type of COVID-19 virus found in 97% of samples all over the world. It is known that radio waves become stronger with mutations, but there is no evidence yet that the virus becomes more virulent, causing clinically worse symptoms or increasing mortality. In general, as viruses mutate and their transmissibility increase, the virulence tends to weaken, but the case of COVID-19 would have to be examined. Moreover, the frequency of mutations occurring in COVID-19 is known to be less than that of the influenza virus. 17 SARS is caused by SARS-COV-1, MERS by MERS-COV, and COVID-19 by SARS-COV-2. Each belongs to the same coronavirus family but is a different virus. 18 There were four cases of influenza pandemics: Spanish Flu (H1N1), Asian Flu (H2N2) from 1957-1958, Hong Kong Flu (H3N2) from 1968-1969, and swine flu (H1N1) from 2009. The subtype of influenza A virus that caused the flu are written in parentheses. 19 The SARS-COV-2, the virus responsible for COVID-19, and the H1N1 influenza virus, which caused the Spanish flu, have many similarities. However, there are many differences. For example, the environment at that time is very different (e.g., population density, degree of transmission and time it took for transmission, socio-cultural factors, etc.) as well as the response of mankind (e.g., it was during World War I, people’s understanding of new infectious diseases was low so nationwide lockdown or strict social distancing did not take place, and only limited measures were taken in some countries). However, regardless of the different epidemiological aspects, the Spanish flu has many implications for the current society 100 years later.

Figure 6

The “Spanish” influenza lasted for about two years, forming three curves in total, and then slowly disappeared, coexisting with humanity for decades. About one-third of the world’s population (estimated at about 1.8 billion at the time of 1918) has been reported to have been infected in two years. The spread of the virus stopped without causing more infection because ma­ jority of the elderly population infected by similar types of influenza viruses formed cross-immunity that prevented further infection.

Figure 5: The mortality rate per 1000 people in the UK at the time of the 1918-1919 Spanish Influenza Pandemics (Source: Jordan E, 1927).

seen that the virus spread from eastern U.S. ports to Europe through a U.S. military fleet that had sailed to take part in World War I, as shown in Figure 6, and then spread to parts of Africa, Asia and Oceania (Dotted Line 2-5). Thus, the first curve was formed during several months in summer of southern hemisphere from March 1918, when the spread was not yet global. This refers to the leftmost curve out of the three curves shown in Figure 5. As seen from the case of UK, the mortality rate was not so high. However, scholars perceive that the virulence became much stronger as a substantial level of mutation occurred in the virus that spread to Europe. Moreover, it is understood that the mutated virus became much widespread while creating a second curve since October of the same year, due to seasonal effects (see Line 2-7 in Figure 6). The death toll from the second curve was significantly higher than that of the first curve, accounting for approximately 70% of all deaths which occurred at that time (see Figure Figure 5 models the spread of the Spanish influenza virus (H1N1) in the Unit­ ed Kingdom in 1918-1920. The Y axis indicates deaths from influenza and pneumonia, one of its complications. It is useful to look at Figure 6 together with Figure 5, which shows how the virus spread geographically as time changes. Opinions vary on where the Spanish influenza originated from (re­ ferring to the dotted line in Figure 6 marked as “?”). However, there seems to be little disagreement about the continuous spread of the influenza around the world after it spread to the eastern part of the U.S. from the western region 5). Afterwards, the pandemic continued on for about two years as the third (the dotted line marked as “0” in Figure 6) in early 1918. At that time, it is

curve took place in 1919.

20 Opinions are divided among scholars on the origin. Some of the mentioned names are China or other Asian countries, France, the U.S., and Spain. 21 For decades after 1920, it has gradually weakened as it coexisted with humankind. Please refer to Figure 8 in the second special periodical.

Figure 7: The mortality rate per 100,000 people from influenza and its complications, pneumonia, in the United States from 1911-1918 (straight line) to 15-54 years of age in 1918 (pending line), shows that the mortality rate from influenza among young age groups is significantly higher than that of 1911- 1917 (dotted line) before Pandemics (Source: Grove RD, 1968).

Figure 7 shows that majority of deaths in 1918 occurred in younger age groups and children under the age of five. The reason for the low death rate in the elderly population caused by the influenza pandemic is attributed to the cross-immunity described earlier. The number of deaths at that time varies somewhat from scholar to scholar, with estimates ranging from as little as 20 to 30 million to as many as 80 to 100 million. In general, 40 to 50 million deaths are most frequently cited. The per capita death rate in developing countries in Africa and Asia (especially India, China, Pakistan, and Sub-Sa­ haran African countries like Nigeria) is more than several times higher than the number in developed countries in Europe and North America. Thus, it is estimated that Asian and African countries had accounted for about 80% of total deaths.

Figure 8 shows the trend of mortality rate in 14 European countries at the time. Each country is very helpful in understanding the actual aspects of epidemiological curve(s). At that time, influenza pandemic took place in 14 European countries with difficult epidemiological curves. Some countries have single curves while others have two or multiple curves. However, they share the common feature of having the largest curve during the spread of infection in the fall of 1918.

Figure 8: The death rate per 10,000 people in 14 European countries in 1917-1921. These figures well-represent the dynamics of the 1918 Influenza Pandemic. (Source: Severine Ansart, etc. 2009.)

09 Global Care, COVID-19 Report

B. Observation for Scenario elicitation • The following is the summary of obser­ vations from the influenza pandemic 100

who will have to continue the war against COVID-19 until vaccine development and mass production takes place in the future, is “how many curves in which forms will come in the future?” (particularly for Group 1 countries in Table 2, “when will the first curve come?”). years ago to derive scenarios for COVID-19 • An interesting outlook was published some time ago (on April 30) in the Viewpoint of the Center for dynamics. • First , different epidemiological curves can occur in different countries. • Second , the degree of spread and death of infection is the same, 100 years ago or now, in that it is caused by the results of three interactions among “the nature of the virus, the human behavioral factors, and the environmental factors.” However, 100 years ago, the nature of the virus (high mortality from second curves caused by highly virulent viruses due to mutation) and environmental factors (greater geographic spread of second infections that occurred during the fall) were seen to have played an important role. On the other hand, the nature of the virus (the proportion of asymptomatic patients being almost 15% out of entire patients with COVID-19) and the human behavioral factors (lockdown policies or so­ cial distancing which took place worldwide) were influential in the case of COVID-19. Several scholars have reported mutations of the COVID-19 virus. Fortunately, such mutations did not worsen patient’s clinical symptoms or increase the fatality rate. • Third , the climate factor out of the envi­ ronmental factors played an important role in the “Spanish” flu but was less influential in COVID-19. However, today’s social structure, which is tightly linked with high population density and globalization, is one of the main reasons why mankind is strug­ The scenario in Figure 9 predicts how COVID-19 will be developed and what kind of epidemiological gling in the war against COVID-19. • Fourth , the spread of infection in 1918 features will be portrayed based on the analysis of influenza pandemics that have been around since the early 20th century. It was developed based on the climatic zone in the Northern Hemisphere. It is predicted stopped at about one-third of the entire that countries in the Southern Hemisphere will have similar patterns, only with a time difference of about population because of the cross-immunity six months. created from various types of influenza viruses that existed before. However, such The first scenario is when a large curve is continuously repeated. Each time a curve is made, lockdown cross-immunity cannot be expected in the or social distancing must be strengthened. However, when such measures are mitigated to revive the econ­ case of COVID-19, as it is a completely omy, the curve that worsens again. Spain and France have seen two relatively large curves so far, which is new virus. There is high possibility that the spread of the virus is likely to continue until consistent with the beginning of this scenario. herd immunity is formed (probably until The second scenario is when a very large curve is formed in the fall of 2020, followed by several 60-65% of the entire world population are small curves. This means that the situation will be similar with the Spanish influenza pandemic. We should infected). Therefore, vaccine development see if there will be a country moving into this pattern due to economic revival, seasonal impact, etc. in the is a very important strategic tool for us. • Fifth , at the time of Spanish influenza future. Pandemics 100 years ago, the mortality rate The third scenario shows that after a large curve has passed in the first half of 2020, the degree of of young people was very high. Therefore, infection remains relatively low. Therefore, the situation does not deteriorate without reintroducing many deaths occurred in India and other de­ lockdown or social distancing. It is similar with the present situation of New Zealand or Taiwan. veloping countries. However, in the case of COVID-19, a substantial number of deaths Box 1 shows the relevance between the countries in Table 2 and the above three scenarios. occurred in developed countries that have large elderly population. It will be important to find out how the elderly population react to the vaccine under development, particularly as they are known to have low immunity effects from vaccines.

C. Prospects after the first curve • One of the most important questions for us

Infectious Disease Research and Policy (CIDRAP) published by the University of Minnesota. Dr. Marc Lipsitch, Harvard epidemiologist, also contributed to the writing. • Viewpoint presents three possible epidemiological curve scenarios for COVID-19 that may appear in the future (see Figure 9).

Figure 9: COVID-19 Epidemiological Scenarios Scenario 1: Very large curves appear continuously (Social distancing/ lockdown needs to be repeatedly strengthened and eased) Scenario 2: Very large curves appear this fall/winter, as in the case of the Spanish flu, followed by small curves. Scenario 3: Since the first big curve, only small curves continue to appear, thus may not be necessary enhanced social distancing or lockdown.

(Source: Center for Infectious Disease Research and Policy, Univer­ sity of Minnesota, U.S. 30 Apr, 2020)

th

22 In the early days of COVID-19, scientists predicted that virus activity and infection will be reduced once the Northern hemisphere enters summer and becomes hot and humid. However, until recently, scientists did not find any clear evidence or data supporting such prediction.

Box 1

It is likely that the Group 1 countries in Table 2 will develop as predicted in the first or second scenario or in its modified forms. The ideal model for group 2 countries in the future will be scenario 3. Group 3 countries are already showing second curves, thus it remains to be seen whether a) they will take the path of Scenario 2, b) they will proceed with a hot and cold spell as seen in Scenario 1, or c) they will be able to portray Scenario 3 after all challenges have been overcome. Of course, many countries are more likely to have a slightly altered or hybrid pattern than typical pat­ terns shown in scenarios 1, 2 and 3.

There is one thing in common among the three scenarios: multiple curves can occur, not just one or two curves over the course of two years.

I would like to conclude by saying that this kind of scenario work could help develop plans by stimulating scientific imagination, regardless of whether it actually happens or not.

References

Dissertation/Books

• C.W. Potter, A history of influenza, Journal of applied microbiology, Vol 91, 572-579, 2001 • Grove RD, Vital statistics rates in the United States: 1940–1960. Washing­ ton: US Government Printing Office, 1968. • Isabella Eckerle, SARS-COV-2 seroprevalence in COVID-19 hotspots, Lancet, 6 July 2020 • Jeffery K. Taubenberger, etc, 1918 Influenza: the Mother of All Pandemics, Emerging Infectious Diseases, Vol.12, 1 Jan 2006 • John P.A. Ioannidis, The infection fatality rate of COVID-19 inferred from seroprevalence data, medRxiv, 14 Jul 2020 • Kristine A. Moore and Marc Lipsitch, COVID-19: The CIDRAP Viewpoint, Part 1: The Future of the COVID-19 Pandemic: Lessons Learned from Pandemic Influenza, University of Minnesota, 30 April 2020 • Linda Nordling, The pandemic appears to have spared Africa so far-Scien­ tists are struggling to explain why, Science, 11 Aug 2020 • Marina Pollán on behalf of the ENE-COVID Study Group, Prevalence of SARS-COV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study, Lancet, Vol 396, 22 Aug 2020 • C. Murray. etc, Estimation of potential global pandemic influenza mortality on the basis of vital registry data from the 1918-20 pandemtic: a quantitative analysis, Lancet, Vol 368, 23 Dec 2006 • Se´ verine Ansart, Mortality burden of the 1918–1919 influenza pandemic in Europe, Influenza and Other Respiratory Viruses, 3, 99–106, 8 April 2009 • Sophie Uyoga, Seroprevalence of anti-SARS-COV-2 IGG antibodies in Kenyan blood donors, medRxiv, 27 Jul 2020

Website

• GAVI (The Global Alliance for Vaccines and Immunizations) • https://www.gavi.org/covid19/covax-facility

4. Concluding Remarks

Acknowledgements

Articles

South Korea, which had maintained a low level of new patients since the first curve, has recently strengthened social distancing measures with the formation of the second curve. Intensive discussions are underway regarding whether to upgrade the social distancing policy to level 3, which is considered as the last resort.

We have time-travelled to 100 years ago and introduced an example of epide­ miological scenarios because we need a lot of scientific facts and evidence to establish an evidence-based policy. Yet, regarding COVID-19, we (not just Ko­ rea but the entire world) are still at a stage of “learning by doing,” thus having to use scientific imagination if needed.

When asked about her thoughts after 6 months have passed since the war on COVID-19 on July 20, Jeong Eun-kyung, the director of the Korea Centers for Disease Control and Prevention, said “Personally, I think we’ve come about 10 kilometers during this marathon. But I feel as if I sprinted as fast as I could the whole time, just as one would when he or she is running for a 100m race.” The war on COVID-19 is an unprecedented reality that requires the entire na­ tion to participate and run the marathon together. To complete the race suc­ cessfully, each participant must conserve his or her strength, become seasoned runners, and build national solidarity.

The last special periodical will be written after some time passes, just like this article, and it is likely to focus on the remaining tasks and exit strategies as we pass the turning point of this marathon.

We thank Zion KIM, Intern in Global Care, for English translation, and Mhin­ jine KIM, MHS Univ. of Illinois at Chicago, Division of Health Policy and Administration, for translation review.

• WHO COVID situation update • https://covid19.who.int/ • WHO Global seroprevalence survey-solidarity 2 • https://www.who.int/emergencies/diseases/novel-coronavirus-2019/glob­ al-research-on-novel-coronavirus-2019-ncov/solidarity-2-global-serolog­ ic-study-for-covid-19 • Worldometer • https://www.worldometers.info/coronavirus/

• Aaron Steckelberg, etc. These are the top coronavirus vaccines to watch, Washington Post, 25 Aug, 2020 • Cho, Eura, Economy first than disease by president in Brazil. Dongailbo, 31 Mar, 2020 • Daily money, SK chemical contracted with AstraZeneca for Convid vaccine production, 24 Jul, 2020 • Hilary BRUECK, Antibody tests around the world suggest very, very few people have • built immunity to the coronavirus, Business Insider, India, 11 JUL, 2020, • Linda Nordling, The pandemic appears to have spared Africa so far - Scien­ tists are struggling to explain why, Science, 11 Aug 2020 • Sinéad Baker, The architect of Sweden’s no-lockdown strategy said up to 30% of its population could now be immune to COVID-19, a claim backed up by little data, Business Insider, 18 Aug 2020 • The conversation, Why we can’t tell if warmer weather slows down the spread of coronavirus, 23 July 2020

Global Care Speical Report

5. Covid-19 Exit Strategy and One Health

• Clinical three-phase tests of the COVID-19 virus indicate that the effectiveness of the vac­ cine was higher than expected at 95%, setting the stage for the exit strategy from COVID-19. High-income countries that have sufficiently secured the vaccine are expected to be able to form herd immunity by the second half of 2021 through vaccination. However, low-income countries that are not able to secure vaccines are expected to be able to form herd immunity by 2023. • In order to determine whether the vaccine can be fully established as a game changer, we need to observe two or three technical problems. It is necessary to get answers on whether the vaccine’s immunity will last at least a year, what the percentage of asymptomatic infections that vaccine cannot prevent is, and whether the vaccine will be effective for mutated viruses. Many studies are currently being conducted simultaneously with large amounts of vaccinations around the world. Therefore, possibly in a few months’ time, we can anticipate answers to the questions above.

• While access to vaccines is disproportionate across countries, purchasing vaccines through Covax is currently the only option in low-income countries. Considering that this pandemic is a global problem rather than a regional one, win-win situation through global solidarity and cooperation is urgently needed. • New infectious diseases have been on the rise during the past 70 years. Sixty percent of them are due to zoomotic diseases. Major causes of the new infectious disease include increased con­ tact among wildlife, livestock, and people due to reduced wildlife habitat. Other causes include loss of biodiversity, industrialized non-welfare livestock systems aimed at mass production, and increased global exchanges (travel and transportation of goods). A one-health strategy is now required, which is a strategy that takes not just human health but animal health and a healthy natural environment into consideration. The human race are given the task of improv­ ing and expanding the one-health strategy in its early stages.

1. Opening words

18 Jan 2021

th

The disease prevention effectiveness of the COVID-19 vaccine, which had been developed amid global at­ tention and expectations, is higher than expected. Moreover, discussions on exit strategies are in full swing as The views and opinions expressed in article are those vaccinations begin after obtaining approval from the Food and Drug Administration (FDA). I finished writing of the author and do not necessarily reflected the offi­ the 4th article in early September last year, thinking that if the exit strategy is realized, I could write the last cial policy or position of Global Care. 5th article of the COVID-19 special series. As I am writing the final article on COVID-19 exit strategy in the beginning of the new year, I feel much lighter. In this issue, we will look at the effectiveness of vaccine, the Correspondence to: global situation of securing the vaccine, and the prediction (time) of herd immunity formation. Moreover, we Dr. Dong-il AHN, Glabal Care, Seoul, South Korea ahndongil@gmail.com will explore what is needed to prevent new pandemics that may arrive someday.

1 Due to the industrialized mass livestock system, which traps and raises many animals in narrow cages, animals are under a lot of stress, reducing their immunity. As a result, the animals are more vulnerable to infection, and infectious diseases caused by frequent contact opportunities in confined spaces are more easily spread.

2. COVID-19 Vaccine: Game changer?

A) Vaccine Effectiveness Figure 1 shows the current status of the COVID-19 vaccine, which has been approved or are being used by each country as of January 7, 2021. Among them, the United States (US) FDA and the European Union (EU) FDA are globally trusted institutions that apply the strictest standards during the vali­ dation process to ensure the safety of vaccines. Pfizer and Moderna’s vaccine have been approved by both institutions and are currently in use in many countries, including the US, Canada, and Israel. Vaccines produced in China and Russia have been used in limited emergencies in their own countries and several developing countries after obtaining authorization and, in some cases, even before the authorization was obtained.

Among the vaccines listed above, the Pfizer vaccine has completed its scien­ tific verification by publishing their clinical experiment results and data in a trustworthy scientific journal . The Pfizer vaccine belongs to the messenger RNA vaccine family , and its efficacy and side effects are as follows.

Figure 2. Validity after inoculation of the Pfizer vaccine (BNT162b2) (Source: F. Polack et al., 2020.12.16). The x-axis is the period after primary inoculation (date), and the y-axis is the cumulative incidence of patients with COVID-19 symptoms. The red circle indicates the cumulative proportion of patients among those who have been vaccinated, and the blue square indicates the cumulative proportion of patients in the placebo group (which means they are not vaccinated against COVID-19). If marked black in a circle or square, it means a critical patient. The graph in the left-upperhand square is an expanded version of the incidence rate of the first 21 days after inoculation, which shows a difference in the incidence of patients between the two groups from the 12th day after inoculation.

From the 1 round of vaccination and right before the 2nd vaccination (which took place after 21 days passed since the 1 round)

st

Figure 1. Vaccines approved/in use by each country (Source: JoongAng Ilbo, 2021.1.7)

st

7 days after the 2 round of vacci­ nation

nd

B) Formation of herd immunity by vaccines

Over the course of four months from July to November 2020, phase III clini­ cal trials of the Pfizer vaccine were conducted in 152 locations of six countries around the world for approximately 44,000 adult men and women aged 16 and older. As shown in Table 1, the results were 52.4% of vaccine efficacy on the first round of vaccination, and 94.8% during the second round (i.e., double inoculation). COVID-19

Placebo vaccine Vaccine # of patients vaccine group group (non-vacci­ with COVID-19 (BNT162b2) Efficacy nation group) symptoms (%)

(21,669 in total)

(21,686 in total)

52.4%

94.8%

Table 1. COVID-19 Vaccination Validity (Source: F. Polack et al., 2020.12.16)

Here, it is important to understand what 95% of vaccine efficacy means. When comparing approximately 20,000 vaccinated and non-vaccinated groups, nine people showed symptoms of COVID-19 in the vaccinated group, while 172 people did in the non-vaccinated group. This means that the 95% of the patient cases of the symptomatic COVID-19 in the vaccinated group were prevented . However, the extent of asymptomatic patients were not checked in the clinical trials, so it is currently unknown, and efficacy of 95% is limited to the prevention of symptomatic infections. Currently, vaccinations are actively implemented in many countries, and research results of these vaccinations over the course of next few months will reveal the exact effectiveness of the vaccine on infection prevention (i.e., pre­ venting both symptomatic and asymptomatic infections). Clinical trials have not measured how much difference there is in the rate of infection prevention between the vaccination group and the placebo group, but the rate is predicted to be somewhat lower than 95%. This will play an important role in predict­ ing when the vaccines will form herd immunity, and a lot of data is expected to be accumulated over the next few months.

As far as it is known, the efficacy of moderna is about 94% and AstraZeneca is about 70%, which, like Pfizer, represents the preventive effect of symptomatic COVID-19 virus, excluding the prevention of asymptomatic infections. The safety of the vaccine was observed for two months after vaccination in the case of Pfizer, and experts believe it would not be a stumbling block for mass vaccination since there were little to no serious side effects of Grade 4 level.

There are two purposes of COVID-19 vaccinations. The first is to reduce the patient mortality rate by inoculating the high-risk group of COVID-19 infec­ tions and deaths (the high-risk group includes health and medical personnel, and also includes those aged 65 or older and those with underlying diseases), and allowing the health care workers to focus on COVID-19 prevention and treatment activities without fear. The number of people who will be vaccinated with priority varies from country to country, but it is estimated that about 20 percent of the population will be classified as so. The second is to stop the spread of infection by inducing herd immunity through the vaccines. Here we will take a closer look at the second goal: herd immunity.

2 The Moderna vaccine reported its vaccine efficacy to be 94% on the company’s website and the U.S. NIH homepage, but it has not yet been published in a scientific journal. 3 The mechanisms for the action of the messenger RNA vaccine are as follows. Injecting some of the virus’ messenger RNA into the body creates a piece of the virus’s protein after it enters the body’s immune cells, which then causes the body’s immune system to form antibodies and defend against future infections. 4 In order to learn how many COVID-19 asymptomatic infections occurred in both COVID-19 vaccination group and non-vaccination group, PCR tests or antibody tests need to be conducted. However, in order to conclude the clinical trials, which normally takes several years, within months, clinical trials were conducted while skipping these tests. In other words, how effective the vaccine is in preventing symptomatic infections was observed in the clinical trials, yet no degree of preventing asymptomatic infections was observed. 5 For example, the CEO of Pfizer said in a media interview that he expects the vaccine to have at least 50-60% of infection prevention effects on others. 6 Recently, about 42,000 people have received the Pfizer vaccine in Norway as of 16 January 2021, with 29 reported deaths shortly after vaccination. Most of the deaths were 75-year-old elderly with underlying diseas­ es, and a thorough investigation is under way, believing that the process of forming immune response by vaccines may have been a burden on the elderly population.

Figure 3 is a model built to explain the concept of herd immunity. The theory is that as more and more people in the community are immune through

Figure 3. Herd immunization model (Source: Mohammed Al-Betar, 2020.8.27) ● Susceptible, meaning that a person is likely to have future infections due to lack of immunity ● Currently infected ● IImmuned refers to a person who already has immunity ● Indirectly protected means a person who is protected from infection due to the effect of herd immunity, i.e., the beneficiary of herd immunity. On the left is the situation when group immunity is not formed, and on the right is the case when group immunity is formed, showing that four people in blue ( ● ) do not get infected due to the effect of herd immunity

from vaccination to be formed, given that 95% of the vaccines are effective (Figure 4-1), and that 0–25% of Americans are assumed to have antibodies vaccination or natural infections, infections gradually decrease as the infection through natural infection (Figure 4-2). However, as previously described, connection (link) is cut off and new infections cannot occur anymore. The

considering that 95% of vaccine efficacy is limited to the prevention of symp­ picture shows how people who didn’t receive vaccination (four people in blue) tomatic infections and there is the possibility of asymptomatic infections , are protected from infection due to people who have immunity through natural the vaccine’s infection prevention efficacy would be less than 95%. Figure 5 infection or vaccination (in green). The formation of herd immunity is closely presents a more realistic scenario in which, assuming 75% vaccine effi­ cacy on the left side and 50% on the right, the vaccination rates required related to the virus’ reproduction index (R ), and in the case of COVID-19, to form herd immunity are 60-80% and over 90%, respectively. Anthony which is known to have a reproduction index of 2.5, it is known that herd immunity is formed when approximately 60-65% of the population has been naturally infected or vaccinated. However, this rate of 60-65% is only when the vaccine efficacy is 100%. Therefore, the vaccination rate needed for herd immunity (formation) will naturally increase if the vaccine efficacy is not guaranteed to be 100%.

From September of 2020 until recently, McKinsey, a global consulting firm, has released two reports predicting the timing of herd immunity formation in the US through COVID-19 vaccine. Figure 4 shows a scenario in which 45–60% of the population needs to be vaccinated in order for herd immunity

7 In general, about 30% of COVID-19 patients are known to be asymptomatic.

Pouch, a renowned US infectious disease expert, also expressed his opinion in a recent media interview that about 85% of Americans must be vaccinated to form herd immunity.

Based on the above scenario, the McKinsey Report predicted that the U.S. would have an exit from COVID-19 in the third and fourth quarters of 2021 as herd immunity begins to form.

Figure 4. Prediction scenario 1 (US with 95% infection prevention effectiveness of the vaccine): the x-axis repre­ sents the vaccination rate (vaccine coverage), the y-axis on the left represents the efficacy of the vaccine, and the y-axis on the right represents the extent of immunity formation by natural infection (range of current assumed natural immunity). The period to reach herd immunity has been measured by predicting the period required for mass vaccination to take place. This period was estimat­ ed by measuring the vaccination rate required for herd immunity from the percentage of population that has formed immunity from COVID-19 infection (Figure 2) and the vaccination rate required for herd immunity (Figure 3) according to vaccine efficacy (Figure 1). (Source: McKinsey, November 2020).

C) Game Changer

demand needs to be considered. Securing vaccines in developing countries is expected to be substantially slow, thus the vaccination rate in those countries is not expected to reach the necessary level to form herd immunity until 2022-2023. In this pandemic situation, herd immunity at a global scale is ultimately re­ quired, but national vaccine selfishness is feared to be at a significant level. Let’s take a closer look at this.

Figure 5. Prediction scenario 2 regarding herd immunity formation (left: when vaccine infection pre­ vention effectiveness is 75%, right: when the effectiveness is 50%, US) When the vaccine effectiveness is 75%, herd immunity can be expect­ ed when 60-80% of vaccination takes place. When it is 50%, 90% of vaccination needs to take place. (Source: McKinsey, November 2020).

There have been concerns that vaccination immunity formation tends to be poor or slow in the elderly population, considering that the elderly population are the high-risk group when exposed to COVID-19. Fortunately, in the case of Pfizer vaccine, the percentage of patients aged 65 or older was 21% among approximately 40,000 participants of the vaccine clinical trial. It As the status of Korea’s vaccine procurement has been reported in detail through various media outlets is noteworthy that about 95% of vaccine efficacy was shown in the elderly population as it did in young population. The vaccine is quite likely to become a game changer, but there are still some barriers to overcome. First, the important issue is how long the immunity formation from the

3. Securing Vaccines

recently, we will focus on the worldwide supply and acquisition of vaccines. As the pandemic situation did not improve despite national lockdowns in US and other European high-income countries, they have worked ardently at their national levels to develop and purchase vaccines. Many countries have made ag­ gressive investments since early 2020 in vaccine development of leading pharmaceutical companies, and have secured two to three times more vaccines than their own population as a result of rushing to purchase vaccines since middle of last year. These countries include Canada, the US, countries in the European Un­ vaccination will last. Clinical trials have reported ion, Australia, New Zealand, and Japan, as shown in Figure 6. Most low-income countries with the lowest 95% efficacy based on observations made over the course of four months. Scientists predict that the vaccine will be practical if its immunity lasts at least a year or a year and a half, and relevant data is expected to be accumulated through mas­ sive clinical observations in the upcoming future. Second, it is important whether the vaccine will be effective against the variant virus. Re­ cently, COVID-19 variant virus cases have been reported in the United Kingdom (UK) and other countries, which has 70% higher infectibility than the existing COVID-19 virus but has similar toxicity. Therefore, the same level of immunity to the current vaccine is expected. If the vaccine is found to be significantly less effective against the variant virus, the new vaccine is expected to be developed within 6 weeks using the messenger RNA of the variant virus (the development speed is relatively fast as it is the same virus strain). Therefore, experts are quite optimistic regarding the virus mutation. Third, it is important to consider the sense of rejection or resistance against vaccination. About 30 – 40% of the US population have shown objection, and the rate is Figure 6. Global vaccine contract situation (Source: Bloomberg, 2021.1.10) Canada is known to have reported to be higher in European countries. Fi­ the largest number of vaccines compared to the population, as it secured about four times more nally, the imbalance in the vaccine supply and than the total population, while most sub-Saharan African countries seem to have only about 5% of the population.

vaccine contracts have tried to secure up to 20% of the population through Covax , which is co-purchased by WHO, CEPI and Gavi. However, most have secured around 5% of the vaccine so far (The light yellow color in Figure 6 represents less than 50%, whereas majority of countries except some South American and Southeast Asian countries have secured only 5%.)

8 Although it is limited to laboratory setting, there has been a recent announcement that Pfizer vaccines respond well to variant viruses. 9 According to the Guardian, a British daily newspaper, the public funds of high-income countries invested in three pharmaceutical companies, Pfizer, Moderna and Astrogenica, are worth more than 5 trillion won. 10 Covax is part of an international effort to secure vaccines in developing countries led by WHO, CEPI, and Gavi. Please refer to the 4th article for more information.

According to a recent report by the People’s Vaccine Alliance, which includes international relief organiza­ tion Oxfam and others, several high-income countries that amount up to be 14% of the world’s population have bought over 53% of the COVID-19 vaccine, and as a result, 90% of the 70 low-income countries

Based on a research from Northeast University in the US, it has been stated that vaccines should be recognized as public goods and be evenly distrib­ are not expected to be vaccinated until the end of 2021. In fact, 96% of Pfizer’s vaccine that shows 95% uted around the world. As seen in Figure 8, there efficacy and nearly all of the Moderna vaccine were contracted to high-income countries, both of which were priced high and has to be stored at ultra-low temperatures of minus 20 to 70 degrees Celsius, making it difficult for middle- and low-income countries to purchase. AstraZeneca, which was developed with Ox­ ford University, is expected to be available for middle- and low-income countries due to its low price and

has been a comparison between the following two scenarios on mortality prediction: (a) the right bar graph in figure 8 shows the percentage of deaths that can be averted by evenly distributing capability of being stored at general refrigeration temperatures. However, its production capacity is limited, the first 20% of available vaccines to all countries thus only 18% of the world’s population is expected to be vaccinated in 2021.

Figure 7. Prediction of when vaccine acquisition will take place on a level that will enable herd immunity (Source: Economist, 2020.12.18)

The Economist, an international economic and political journal published in the UK, recently announced a prediction of when the supply of the COVID-19 virus will be sufficient to induce herd immunity beyond the early inoculation of high-risk group, as shown in Figure 7. It is predicted that mass vaccination will not be possible until mid-2021 in developed countries, as they would have to solve problems such as transportation and storage of vaccines until a great quantity of them are used in actual medical institutions. Since middle- and low-income countries are currently limited in vaccine supply and also need to secure finances for the purchase of vaccines, it is predicted that mass vaccination in middle-income countries will not take place until late 2021 or mid-2022. Moreover, it is expected that it won’t be easy for low-income countries to secure vaccines until 2022-2023.

None of the low-income countries have obtained vaccines directly through pharmaceutical companies, and majority of them are seeking to purchase vaccines through Covax. WHO or CEPI aims to secure 20% of Covax-participating countries’ population and to begin vaccination in 2021. However, some are skeptical about whether the target can be achieved due to problems such as restrictions on vaccine production, com­ petition with pre-purchasing countries, and securement of finance needed for purchasing.

Figure 8. Differences in COVID-19 death prevention due to vaccine supply con­ ditions (Source: Northeast University, September 2020)

in proportion to their population and prioritizing vaccination of high-risk groups (e.g., older aged persons, persons with underlying diseases, health care workers, etc.) and (b) the left bar graph in figure 8 shows the percentage of deaths that can be averted when the first 20% of available vaccines are mainly distributed to high-income countries and used for mass immunization (which is the scenario that is currently followed). According to this study, the former scenario shows that 61% of the predicted deaths under assumption of no vaccine development can be prevented by vaccination, while the latter scenario results in preventing only 33%. Based on this study, Bill Gates expressed serious con­ cerns regarding the second scenario in which COVID-19 vaccines are preferentially distrib­ uted to the mass population in rich countries who can afford it.

In summary of the COVID-19 vaccine described so far, vaccines are highly like­ ly to act as game changers. However, in the future, the following three things that have yet to be identified should be clar­ ified. In other words, we need to clarify how effective the vaccine is in prevent­ ing infection (as previously described, it is yet to be known whether the vaccine can prevent asymptomatic infection), how long the immunity obtained by vac­ cination will last, and whether it has the same level of prevention effect on the variant virus.

Despite the difficulties of predictive models, business consulting groups are quickly pouring out predictions about when vaccine-induced herd immuni­ ty will be formed, and when the world will return to “normal.” According to an analysis by McKinsey and the Econo­ mist, high-income countries will not be able to get enough vaccinations needed to form herd immunity until the second half of 2021, middle-income countries by mid 2022, and low-income countries by 2023.

11 Dr Krishna Udayakumar, the director of the vaccine tracking institute at Duke University, personally expressed it would be difficult to achieve a 20% target for Covax, and in the case of low-income countries, it would be difficult to secure vaccines needed for herd immunity before the end of 2022.

4. How to prepare for another pandemic in the future

Following the pandemic exit strategy described so far, I would like to finish this article by discussing how to prepare for another pandemic in the future, which is the task of post-COVID-19.

A) Increasing trend of new infectious diseases

After SARS in 2003, the fear of new pandemic of infectious disease devastat­ ing the human society was always present. Even though the swine flu outbreak in 2009 was a pandemic situation, it passed without much impact since the fatality rate from the virus was as low as that of the flu. On the other hand, Ebola, which hit West Africa in 2014-2016, had a very high fatality rate of approximately 70%, but the overall infection rate was relatively low since it could only be infected through direct contact. Therefore, it was contained after being spread to only 10 countries. However, the COVID-19 outbreak has caused an unprecedented global crisis not only in health care, but also in economy and society as a whole, since it has asymptomatic infection and a higher infection rate than a normal flu (compared to the flu with a fatality rate of about 0.05-0.1 percent, COVID-19’s fatality rate amounts up to 0.3-1.0%, which is about 10 times higher). If a new infectious disease with a high infection rate as COVID-19 together with a fatality rate of about 5-10% appears in the future, there will be a formidable situation that cannot be compared to the current COVID-19 outbreak.

Figure 9. Trend of new infectious diseases (Source: E Johns, 2008)

As shown in Figure 9, the incidence of new infectious diseases has continued to increase over the past 70 years, and about 60% of them are attributed to zoonosis. Zoonosis is an infectious disease that occurs in

B) One Health

humans, but there has been reported incidents. In any case, even if human infection occurs from animals, the virus is mostly destroyed by human immu­ nity, and human-to-human transmission generally does not occur. However, there are cases where human-to-human infection occurs very effectively (SARS, MERS, etc.), and in worse cases, pandemic situation occurs. Thus, the fundamental cause of new infectious diseases is the increased direct or indirect contact between wild animals and humans (through livestock), which causes the virus that inhabits wild animals to be transmitted to humans (which is known as spillover) and create serious situations.

Figure 10. Causes of novel infections (Source: Loh et al 2015)

Figure 10 quantifies the factors that cause the outbreak and spread of new in­ fectious diseases. The biggest impact on the development of new infectious diseases is the loss of wildlife habitats as forests are cleared for agricul­ tural land expansion and wood production. Moreover, in a large-scale industrialized livestock system for mass production of meat, which is an­ imal protein, chickens, pigs and cattle are raised under great stress, and increased contact in concentrated spaces leads to increased development and easy spread of infectious diseases (agricultural industry changes). As loss of biodiversity takes place due to forest destructions and large-scale livestock industry environment, virus that lives in wild animals is easily moved to livestock and farm animals (spillover), thus creating diseases.

These new infectious diseases are spreading rapidly around the world due to increased international travel and commerce activities, which is the third important factor in promoting new infectious diseases as seen in Figure 10 (international travel and commerce).

One Health’s objective is to provide optimal health for people, animals, and the natural/environment by addressing the ecological issues that may be both animals and humans due to viruses that live in natural hosts such as the underlying cause of human infections (e.g., occurrence of new infectious bats which transfers to chimpanzees, monkeys, etc., then infect chickens, diseases due to loss of wildlife habitat and biodiversity due to forest destruc­ pigs, cattle, etc., before eventually infecting humans. Direct infection in tions), rather than just providing public health monitoring and responses. As humans may occur directly from wild animals. HIV is believed to have shown in Figure 11, One Health aims to maintain human and animal health as initially spread to humans through infection of chimpanzees, Bird Flu due well as a healthy ecosystem, and Figure 12 is a more detailed schematization to chickens, SARS from Viverridae, and MERS from camel, then infections of its mechanism. were spread from person to person. In the case of COVID-19, it is predicted that the virus was spread from Pangolins to humans. Viruses that used to As explained above, the virus, which used to live in wild animals through be parasitic on natural hosts such as bats are rarely directly transmitted to natural destruction, spreads to livestock and humans, causing zoonosis. In

12 As wild animals move to areas where people or livestock live (or vice versa) due to loss of habitat, there is more contact between wildlife and people or livestock, and the virus of wildlife spreads to livestock and humans.

Figure 11. One Health model (Source: United Nations Environmental Program, 2020)

Figure 12. Outbreak mechanism of new zoonosis due to population growth and natural destruction (Willam Kareshi,etc, Lancet, 2012)

livestock or wild animals in order to prevent their spread. Some infectious diseases such

rare cases, virus is transmitted directly to humans without being transmitted from wild animals through livestock. In addition, the as avian influenza, foot-and-mouth disease, and swine fever are monitored and disposed at a spread of the virus to wild animals, livestock, and humans often occurs through vectors such as mosquitoes and mites. Trans­ mission through insect vector is known to have increased due to climate change.

certain level, but these actions are often limited to advanced countries, and many developing countries cannot properly implemented necessary actions due to government restrictions and weak finances and administrative power. Fourth, safety management of livestock and farms need to be strengthened and the system needs to be converted to welfare-type livestock structure. As we have seen earlier, the non-welfare livestock structure, which Let’s take a look at how the One Health approach will prepare for aims to mass-produce animal proteins, will inevitably increase the risk of new infections in another pandemic in the future. The four strategies emphasized livestock animals due to the stress they receive and the loss of biological diversity. Although in an article titled “Ecological-Economics for Pandemic Pre­ these objectives may seem a little far-fetched in developing countries, the introduction of vention” published in Science in July 2020 are based on One welfare-based livestock industry is globally needed. However, it is a major concern as it is Health, which is summarized as the following. First, we need also not easy to expect high-income countries to reach this point (as pandemic is ultimately to reduce destruction of nature and forests. Although logging created as new zoonosis, which occurs in one corner of the globe, is spread throughout the and land cultivation (or reclamation) have been widespread for the expansion of the wood industry and agricultural land as a part of development policy, the COVID-19 pandemic and its unprec­ edented socio-economic damage are fundamentally reflective of development that damages nature and forests. About 10 trillion won needs to be invested to halve logging and clearing that is going on around the world, but economic losses from COVID-19 Personally, it is a bit saddening to finish the “Infectious Diseases in the Age of Globaliza­ are hundreds of times more than this. Therefore, a fundamental shift or reconsideration of development framework is needed . Second, restrictions and regulations on import and export of wild animals should be strengthened. While poor countries When I wrote the first issue at the end of February last year, I was wondering whether the such as Africa hunt wild animals for food in order to lessen starvation, many countries including the US, Europe, and China

world).

5. Leaving Words

tion, and Globalization of Infectious Diseases” series, which was planned to be published over five articles, but I also feel relieved to finish this series.

virus would literally take over every corner of the world, or whether a turning point could emerge in the near future. The COVID-19 virus, without exception, very brutally scrawled raise or eat wild animals for other purposes. The US is the largest all over the world, and almost all of the countries collapsed in front of its power, surren­ importer of wild animals, and China’s wildlife farm has an econo­ dering with a white flag. Then on December 8 , the first counterattack by mankind was initiated , when the world’s first COVID-19 virus vaccine was inoculated in the UK to my of more than 20 trillion won a year, with 15 million people reportedly working in wildlife farms or other related industries. The origin of COVID-19 is also known as Wuhan’s seafood mar­ ket, so it is necessary to strengthen regulations on handling wild The exit strategy is in place, but we must solemnly think about the question of how the animals, prohibit smuggling, and strengthen regulations related to world will prepare for a new virus attack that may come one day after COVID-19. In order importing and exporting. However, the activities and budgets of international organizations and NGOS dealing with these issues

84-year-old Mr. Curlway.

th

to prevent future pandemics, we should start with a heavy reflection on human civilization that has been developing together with the conquest of nature, as many scholars have are very weak, so it is urgent to strengthen this part in the future. discussed. We need to turn our eyes away from a public health approach or scientific Third, measures should be taken to strengthen the moni­ toring system of common infectious diseases (zoonosis) in

solution, and should humbly prepare for the post- COVID-19 era with a mentality that calls for coexistence with nature.

13 In general, when 25% of forests disappear, it significantly increases the likelihood of people or livestock coming into contact with wild animals. It has been argued that forest destruction should be discontinued based on studies that showed using 10 trillion won per year to stop logging (i.e., to compensate for economic losses from logging bans or restrictions) could significantly reduce risk in 40% of high-risk regions where virus in wildlife animals can be transmitted to humans or livestock. 14 Government should pay compensation to farmers when destroying livestock, yet in low-income countries, governments often cannot easily take these measures due to lack of funds. 15 On December 8, the headline of a local daily newspaper was “Humanity’s counterattack begins.”

References

Thesis/Books

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• C.W. Potter, A history of influenza, Journal of applied microbiolo­ gy, Vol 91, 572-579, 2001 • Grove RD, Vital statistics rates in the United States: 1940–1960. Washington: US Government Printing Office, 1968. • Isabella Eckerle, SARS-COV-2 seroprevalence in COVID-19 hot­ spots, Lancet, 6 July 2020 • Jeffery K. Taubenberger, etc, 1918 Influenza: the Mother of All Pan­ Articles demics, Emerging Infectious Diseases, Vol.12, 1 Jan 2006 • John P.A. Ioannidis, The infection fatality rate of COVID-19 inferred • 조유라, 사람은 언젠가 죽는다며 격리확대보다 경제가 우선이라는 브라질 from seroprevalence data, medRxiv, 14 Jul 2020 대통령, 동아일보, 2020.3.31 • Kristine A. Moore and Marc Lipsitch, COVID-19: The CIDRAP • 데일리머니, 아스트라제나카와 SK케미칼 코로나19 백신 위탁생산 계약 체 Viewpoint, Part 1: The Future of the COVID-19 Pandemic: Lessons 결, 2020.7.24 Learned from Pandemic Influenza, University of Minnesota, 30 • Aaron Steckelberg, etc. These are the top coronavirus vaccines to April 2020 watch, Washington Post, 25 Aug, 2020 • Linda Nordling, The pandemic appears to have spared Africa so • Hilary BRUECK, Antibody tests around the world suggest very, far-Scientists are struggling to explain why, Science, 11 Aug 2020 very few people have • Marina Pollán on behalf of the ENE-COVID Study Group, • built immunity to the coronavirus, Business Insider, India, 11 JUL, Prevalence of SARS-COV-2 in Spain (ENE-COVID): a nationwide, 2020, population-based seroepidemiological study, Lancet, Vol 396, 22 • Linda Nordling, The pandemic appears to have spared Africa so Aug 2020 far - Scientists are struggling to explain why, Science, 11 Aug 2020 • Se´ verine Ansart, Mortality burden of the 1918–1919 influenza • Sinéad Baker, The architect of Sweden’s no-lockdown strategy pandemic in Europe, Influenza and Other Respiratory Viruses, 3, said up to 30% of its population could now be immune to COV­ 99–106, 8 April 2009 ID-19, a claim backed up by little data, Business Insider, 18 Aug • Sophie Uyoga, Seroprevalence of anti-SARS-COV-2 IGG antibodies 2020 in Kenyan blood donors, medRxiv, 27 Jul 2020 • The conversation, Why we can’t tell if warmer weather slows down the spread of coronavirus, 23 July 2020 Website

• 국제백신연합 (GAVI/The Global Alliance for Vaccines and Immuni­ zations) • https://www.gavi.org/covid19/covax-facility • WHO COVID situation update