Herd Immunity and Solutions to the COVID-19 Crisis
All current suggestions to manage the COVID-19 crisis rely to some degree on inducing “herd immunity.” Herd immunity can be achieved if a sufficiently large proportion of the population has either been infected and recovered, now carrying antibodies, or has been vaccinated. Resistance in this proportion results in indirect protection of the rest of the community, even if they have not been exposed or treated themselves. Principles of epidemiology demonstrate that achieving and maintaining herd immunity in the required proportion of the population is the only guaranteed solution to stemming the continued spread of a pathogen.
As the COVID-19 pandemic continues to affect many people economically and personally, strategies for the long-term management of the disease are discussed. Recent studies have shown that after the initial pandemic wave, COVID-19 outbreaks are likely to arise on a recurrent, potentially annual basis. In the absence of an effective vaccine, prolonged or intermittent non-pharmaceutical interventions such as social distancing might have to continue into 2022 to maintain critical healthcare capacity 1.
Policymakers and industry are thus much invested in the rapid development of a vaccine, even though the details of sufficient testing required to guarantee the safety and the time remaining to potential approval of a candidate are still uncertain. This uncertainty has led to the suggestion of less traditional approaches to the management of the virus. Concepts presented include “letting the disease run its course,” implementing lockdown measures of varying stringency according to the levels of new cases reported, and “variolation.” The latter advocates the controlled infection of low-risk individuals with the virus itself or related strains, which can confer effective immunity. Also suggested is the implementation of human challenge studies to accelerate vaccine development, which will only be of interest, however, once a suitable candidate has completed phase 1 and 2 clinical trials.
Introducing herd immunity
All current suggestions to manage the COVID-19 crisis rely to some degree on inducing “herd immunity,” a concept that, despite its importance in the elimination of infectious disease and significance to health policy, remains under-explained and poorly understood 2. Notwithstanding varying definitions of the phrase “herd immunity” 3, what is generally referred to is the herd immunity threshold: the minimum overall fraction of a population that has to be immune to a disease to reduce the mean number of secondary infections to below one 4. This results in an infected individual passing the virus to, on average, less than one person, causing it to stop spreading and dying out. The number of subsequent cases resulting from a single infectious case is also called the basic reproduction number, R0.
Herd immunity can be achieved if a sufficiently large proportion of the population has either been infected and recovered, now carrying antibodies, or has been vaccinated. Resistance in this proportion results in indirect protection of the rest of the community, even if they have not been exposed or treated themselves. The concept is often used to determine vaccination coverage required for disease control, without the need to vaccinate 100% of a population. This is not only much more practical, but also has economic benefits (saving resources like limited vaccine doses) and, most significantly, guards segments of the population not able to be vaccinated from infection 5. People such as the very young, very old, persons with allergies against vaccine constituents or the immunocompromised can have an increased risk of complications and are thus not immunized in some instances. Still, they can be protected by herd immunity 6.
The fraction of the population needed to be immune to reach the herd immunity threshold directly depends on a disease’s basic reproduction number and can be calculated. The more infectious a pathogen, the higher the R0, the larger the proportion immunized must be to block its spread.
Unfortunately, models of infection dynamics are based on various inaccurate assumptions, including homogeneous mixing of individuals and infection conferring lifelong protection 5.
Many of the parameters required to calculate the herd immunity threshold for COVID-19 accurately are known only with considerable uncertainty, preventing true predictions. Rough estimations of R0 vary between 2 and 6, so using a conservative average of 3, the herd immunity threshold lies at approximately 67% 5. Other studies have found the herd immunity threshold for individual countries outside of China to vary widely, but most values fall between 40 and 85 %, displaying a mean around just below 70 % 7. Unfortunately, even after six months of the ongoing pandemic, the percentages of people exposed and possessing antibodies are still far below these values. In Wuhan, the origin of the epidemic, or New York City, serological tests have shown that only approximately 10 and 20 % of the population carry antibodies, respectively 8,9.
Principles of epidemiology demonstrate that achieving and maintaining herd immunity in the required proportion of the population is the only guaranteed solution to stemming the continued spread of a pathogen. Reaching herd immunity is thus always central to policy considerations of eradication measures of any infectious disease. Not only do extended lockdowns and social distancing measures have enormous negative consequences on the global economy and are thus unsustainable, but they are also ineffective in the long run. While a short-term suppression of the first wave of the pandemic was aimed at maintaining the number of cases below the capacity of national health care systems, the remaining susceptible population remains vulnerable to equally devastating resurging infections once restrictions are lifted 10. Experience from the Spanish flu pandemic in the United Kingdom has shown, for instance, that three outbreaks of the pathogen were observed in 18 months, with the second wave being by far the most severe [reviewed in 11].
Sophisticated models have shown that social distancing can be very effective at reducing the R0 temporarily, but simultaneously preventing the acquisition of antibodies and the creation of immunity in the population. A modeled 20-week lockdown period showed a reduction in R0 of 60 %; however, the resurgent outbreak after restrictions are lifted was projected to be nearly the same as the primary, uncontrolled pandemic 1. Again, population immunity and the duration thereof was the critical modulator of the future severity of COVID-19 outbreaks in the next few years 1.
Reducing impacts on the way to herd immunity
Some people advocate promoting natural infections to build population immunity as a lasting solution to the pandemic. Despite much-reduced fatality rates observed over time than initially estimated for China, however, the implications of this would be severe. Several modeling studies and the experiences over the last few months have shown that critical care facilities will be overwhelmed even in high-income countries in the absence of non-pharmaceutical interventions 1. Calculations using low infection fatality ratios of 0.6 to 0.7%, which adjust for asymptomatic and undiagnosed infections, indicate that mortality associated with naturally reaching herd immunity could reach 1.3 million deaths in the United States alone 10. Additionally, the extent and duration of immunity is still uncertain, with the World Health Organization recently indicating that not all recovered patients had immunizing antibodies protecting from subsequent infection 11.
Other research specifies that if immunity established through COVID-19 infection mirrors other coronaviruses, lasting around 40 weeks, then annual outbreaks would be very likely. Longer-term protection of up to two years instead favored biannual outbreaks 1. Hence, the global community is still in need of a long-term solution to the COVID-19 crisis if an effective vaccine is still far in the future, and social distancing measures must be lifted to rescue the global economy.
Some researchers have advocated that herd immunity can be reached and maintained without the high cost of several million fatalities if specific targeted strategies are followed. Models proposed by scientists differ slightly but share a similar general tenet. Outlined are multipronged approaches of a) maintaining social distancing measures at a level where R0, or the number of cases, are reduced not to exceed the capacity of the healthcare system, which usually implies b) the need for expanding critical care facilities. Hence, healthcare capacity is a crucial determinant of the measures required 1,10. Lastly, some proposed models further aim to lower the societal impact of infections by dividing the population in high-risk and low-risk cohorts based on age and comorbidities. They suggest the high-risk population to be isolated under additional protective measures. At the same time, the disease is allowed to spread among the low-risk cohorts to provide immunity in this group. This division will continue until the herd immunity threshold for the population as a whole is reached through the exposure of only low-risk individuals 7,10.
In this context, to hasten the attainment of herd immunity and minimize economic costs, the concept of variolation has been cited 12. Despite not being practiced in modern times as safer vaccines have become available, it may be worth deliberating in the absence of an effective vaccine for COVID-19. Variolation entails administering a dose of the live, unmodified virus to low-risk volunteers to stimulate an immune response. There are theories that the administration via a route not usually utilized by the pathogen, such as subcutaneous inoculation in minimal doses, could be safer and lead to less severe disease than natural infection, while still inducing immunity. Correlations between infecting doses of some viruses, such as seasonal human coronaviruses, influenza, and MERS, viral load and disease severity have been documented in some instances 13–15.
Nevertheless, this concept is not based on a solid foundation of data. It is thus fraught with ethical pitfalls when considering a pathogen with the potential to cause as severe a disease as SARS-CoV-2.
Applications for viral variants with reduced pathogenicity
If effective immunity in low-risk individuals could be raised through exposure to a less pathogenic coronavirus strain or an attenuated variant of COVID-19, risks and implications could be reduced considerably. Since there are large numbers of asymptomatic infections recorded, the existence of an attenuated variant of SARS-CoV-2 virus containing deletions in the genes conferring pathogenicity is probable. Subspecies containing naturally attenuating deletions are thought to coexist with more pathogenic types, considering the significant discrepancies in mortality and morbidity observed in different locations around the globe 16–18. In addition, preferential recording and sequencing of viral genomes from patients who sought medical treatment due to severe disease have caused an underrepresentation of mild variants in the genome databases 17. Continued viral evolution may also lead to a natural tendency for the virus to become less pathogenic over time 19. Hence, testing the population for subclinical infections and cataloging genetic diversity of possibly less pathogenic viruses is an integral part of disease surveillance.
An attenuated variant, if found, might not only be applied directly to induce antibodies itself but could also serve as a testing tool in potential human challenge trials for vaccine candidates. Implementation of human challenge trials has been suggested as an essential measure to speed up vaccine licensing.
Under normal circumstances, all vaccine candidates must be assessed using phase 3 clinical trials, involving several thousand participants. These field trials are designed to evaluate the difference in the incidence of disease between groups receiving vaccine and placebo in a natural setting, where many take precautions to avoid infections. Participants must be followed over long periods, so enough people are eventually infected to make statistically valid assessments of the efficacy of the vaccine candidate versus the placebo 20.
In contrast, during human challenge trials, volunteers are administered either a dose of a vaccine candidate or a placebo before being deliberately exposed to the pathogen. Hence participants receiving placebo are infected without any protection and, despite strict medical supervision, are at risk of developing severe disease. Such experiments were completed in the search for vaccines for other infections such as malaria or cholera in the past [reviewed in 21]. Since there is no known cure or effective treatment for COVID-19, in contrast, the ethics are much debated. Any potential ways to reduce risks to participants are a non-trivial consideration should challenge trials be implemented 22. Hence, the search for a naturally attenuated subspecies of SARS-CoV-2 to use as a challenge virus is highly advisable.
Some researchers have speculated that increasing genetic diversity and continued evolution of a heterogeneous population of SARS-CoV-2 virus variants will thwart the acquisition and protective effects of herd immunity due to a lack of antigenic cross-reactivity 16. However, other scientists have warned against over-interpreting the epidemiological and pathological significance of mutations observed in the SARS-CoV-2 genome, stating that single variations seldomly impact highly conserved antigenic regions 23,24
This is further supported by evidence showing a certain amount of antigenic cross-reactivity even among different species of coronaviruses. Common seasonal coronaviruses (OC43, 229E, NL63, HKU1) that have been circulating in the population are considered sources of possible partial immunity 7. Limited cross-reactivity has been reported among betacoronaviruses 15.There has also been moderate cross-neutralization activity between convalescent sera of SARS-CoV and SARS-CoV-2 patients, indicating a potential small degree of immunity provided by the previous infection with the other virus 25. A level of protection against SARS-CoV-2 infection has been demonstrated by some anti-SARS-CoV neutralizing antibodies in vitro 26. In addition, monoclonal antibodies targeting parts of the S protein of SARS-CoV have shown broadly neutralizing activity against different strains of the virus [reviewed in 15], making the evolution of antigenically distinct strains of SARS-CoV-2 unlikely.
Thus, epidemiological principles favour the herd immunity approach for mitigating the impacts of COVID-19. Despite the lack of direct evidence for SARS-CoV-2, however, the threat of immune enhancement induced by cross-reacting antibodies and the possibility of antigenic escape through mutation should be kept in mind. Policymakers will continue to face the difficulty of making decisions in the absence of reliable and complete data for some time. Only through ongoing monitoring of population seroprevalence, the incidence of infections and disease will a full picture emerge in the future.
1. Kissler, S. M., Tedijanto, C., Goldstein, E., Grad, Y. H. & Lipsitch, M. Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science (80-. ). 868, eabb5793 (2020).
2. Betsch, C., Böhm, R., Korn, L. & Holtmann, C. On the benefits of explaining herd immunity in vaccine advocacy. Nat. Hum. Behav. 1, 1–6 (2017).
3. John, T. J. & Samuel, R. Herd immunity and herd effect: New insights and definitions. Eur. J. Epidemiol. 16, 601–606 (2000).
4. Georgette, N. T. Predicting the herd immunity threshold during an outbreak: A recursive approach. PLoS One 4, (2009).
5. Randolph, H. E. & Barreiro, L. B. Herd Immunity: Understanding COVID-19. Immunity 52, 737–741 (2020).
6. Kim, T. H., Johnstone, J. & Loeb, M. Vaccine herd effect. Scand. J. Infect. Dis. 43, 683–689 (2011).
7. Kwok, K. O., Lai, F., Wei, W. I., Wong, S. Y. S. & Tang, J. W. T. Herd immunity – estimating the level required to halt the COVID-19 epidemics in affected countries. J. Infect. 80, e32–e33 (2020).
8. Wu, X., Fu, B., Chen, L. & Feng, Y. Serological tests facilitate identification of asymptomatic SARS-CoV-2 infection in Wuhan, China. J. Med. Virol. 0–3 (2020). doi:10.1002/jmv.25904
9. Amid Ongoing COVID-19 Pandemic, Governor Cuomo Announces Results of Completed Antibody Testing Study of 15,000 People Showing 12.3 Percent of Population Has COVID-19 Antibodies. Available at: https://www.governor.ny.gov/news/amid-ongoing-covid-19-pandemic-governor-cuomo-announces-results-completed-antibody-testing. (Accessed: 24th June 2020)
10. Akamatsu, T., Nagae, T., Osawa, M., Satsukawa, K. & Sakai, T. Can a herd immunity strategy become a viable option against COVID-19? A model-based analysis on social acceptability and feasibility. medRxiv 1–18 (2020). doi:https://doi.org/10.1101/2020.05.19.20107524
11. Zha, T. & Kopecky, K. Impacts of COVID-19: Mitigation Efforts versus Herd Immunity. Fed. Reserv. Bank Atlanta, Policy Hub (2020). doi:10.29338/ph2020-03
12. Cullerne Bown, W. Exit Route? The Case for Variolation Against COVID-19. SSRN Electron. J. (2020). doi:10.2139/ssrn.3587397
13. Paulo, A. C., Correia-Neves, M., Domingos, T., Murta, A. G. & Pedrosa, J. Influenza infectious dose may explain the high mortality of the second and third wave of 1918 1919 influenza pandemic. PLoS One 5, 1–8 (2010).
14. Nam, H. S. et al. High fatality rates and associated factors in two hospital outbreaks of MERS in Daejeon, the Republic of Korea. Int. J. Infect. Dis. 58, 37–42 (2017).
15. Huang, A. T. et al. A systematic review of antibody mediated immunity to coronaviruses: antibody kinetics, correlates of protection, and association of antibody responses with severity of disease. medRxiv 2020.04.14.20065771 (2020). doi:10.1101/2020.04.14.20065771
16. Danchin, A. & Timmis, K. SARS-CoV-2 variants: Relevance for symptom granularity, epidemiology, immunity (herd, vaccines), virus origin and containment? Environ. Microbiol. 22, 2001–2006 (2020).
17. Armengaud, J. et al. The importance of naturally attenuated SARS-CoV-2in the fight against COVID-19. Environ. Microbiol. 22, 1997–2000 (2020).
18. Yao, H. et al. Patient-derived mutations impact pathogenicity of SARS-CoV-2. medRxiv 2020.04.14.20060160 (2020). doi:10.1101/2020.04.14.20060160
19. Danchin, A. & Marlière, P. Cytosine drives evolution of SARS-CoV-2. Environ. Microbiol. 22, 1977–1985 (2020).
20. Eyal, N., Lipsitch, M. & Smith, P. G. Human Challenge Studies to Accelerate Coronavirus Vaccine Licensure. J. Infect. Dis. 1–5 (2020). doi:10.1093/infdis/jiaa152
21. Nguyen, L. C. et al. Evaluating use cases for human challenge trials in accelerating COVID-19 vaccine development. 1–26 (2020). doi:10.31219/osf.io/7gc4b
22. Jamrozik, E. & Selgelid, M. J. COVID-19 human challenge studies: ethical issues. Lancet. Infect. Dis. 3099, 18–20 (2020).
23. Grubaugh, N. D., Petrone, M. E. & Holmes, E. C. We shouldn’t worry when a virus mutates during disease outbreaks. Nat. Microbiol. 5, 529–530 (2020).
24. Tang, X. et al. On the origin and continuing evolution of SARS-CoV-2. Natl. Sci. Rev. (2020). doi:10.1093/nsr/nwaa036
25. Ou, X. et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat. Commun. 11, (2020).
26. Jiang, S., Hillyer, C. & Du, L. Neutralizing Antibodies against SARS-CoV-2 and Other Human Coronaviruses. Trends Immunol. 41, 355–359 (2020).