If enough people are protected, a pathogen cannot spread

Globally there is much discussion about SARS-CoV-2 and herd immunity. Herd immunity is quite simply safety in numbers, allowing both vulnerable and healthy people to be protected. Herd immunity against COVID-19 would allow social distancing and other protective measures to be reduced and for life to potentially go back to the old normal. It’s usually a term associated with vaccination programs, but it has started to be used in connection with natural SARS-CoV-2 infection. When enough people within a population are protected, then a pathogen cannot continue to spread. Vulnerable people sometimes can’t be vaccinated, for example those taking immune suppressants, or those with pre-existing medical conditions. But for herd immunity to be achieved, a threshold of individuals within the population must be reached.

What is the herd immunity threshold?

If you have been following the news on COVID-19 I imagine you would have heard the term R0 quite a lot -pronounced R naught. This is the basic reproduction number, it’s the number of secondary infections that result from 1 infectious person, and thus R0 is a pathogens indicator of contagiousness [1]. The higher the number, the more contagious a pathogen is. For herd immunity to SAR-CoV-2, the threshold value ranges from 67% – 83% of the population. So how can this be reached?

Can herd immunity be reached through natural infection?  

While many countries introduced a lockdown to minimise non-essential travel and thus transmission, not all countries followed. There was a huge amount of variation across the world [2]. In particular South Korea, Nicaragua and Zanzibar didn’t introduce a lockdown at all [3].

Sweden took a different approach to its Nordic neighbours Vulnerable people were shielded, schools were closed to children over 16-years-old and gatherings of more than 50 people were discouraged, However bars, restaurants, and other public spaces remained open. While individuals were encouraged to socially distance, it was more voluntary. Sweden does have an established health care system and plenty of space for individuals to distance themselves compared to other countries, but their policy caused controversy nonetheless. That aside, could a byproduct of this approach be that Sweden is able to reach

“I herd that I’m protected if enough people around me have immunity.” (J. Self-Fordham/CRL)

herd immunity via natural infection? Five months into Europe’s pandemic, testing was carried out and only 6% of the population in Sweden was found to have antibodies capable of binding to SARS-CoV-2, according to Swedish Public Health Agency research [4]. Given that antibody detection can be unreliable, this figure is most likely is higher. Also, it doesn’t consider the level of cellular immunity of individuals, individuals may have immunological memory (in the form of B cells capable of producing antibodies) but protection will not be clear unless individuals are re-exposed. Still ~6% is still no-where close to the herd immunity threshold of 67% – 83%.

Trying to reach herd immunity via natural infection is fraught with obstacles. Most importantly it’s not clear what level of illness becomes protective and in turn who is fully protected. Not to mention the large number of possible fatalities if the world allowed SARS-CoV-2 to spread uncontrollably. One estimate that combines the case fatality rate (CFR) and infection fatality rate (IFR) with a R0 of 3, suggests the consequence of reaching herd immunity through natural infection would result in deaths in excess of 30 million globally [5]. Of course, this approach would be unethical and devastating for countries where healthcare systems would be overwhelmed. What’s the alternative?

Vaccination

The most scientifically proven and safe route to reach herd immunity is vaccination, and globally the race is on! Many countries across the world are testing novel vaccinations. Sir Jeremy Farrar, the director of the Welcome Trust speaking to the BBC world news on the 5th August is confident that vaccines will be available both in 2020 and 2021 in the UK [6]. Meanwhile in the US Operation Warp Speed, a collaboration of both public departments and private sector biopharmaceutical companies are working to produce a vaccine for January 2021 in the US [7]. As a pre-clinical research scientist involved in testing early stage vaccines, when vaccination is discussed, my mind is filled with all sorts of questions like; how does the vaccine work? How much protection does the vaccine provide? How many vaccinations will I need to have some protection? Will the vaccine be available? It’s the answers to these questions which will also affect the ability of reaching global herd immunity. Let’s start at the top.

How does a SARS-CoV-2 vaccine work?

Globally there are several strategies to SARS-CoV-2 vaccines. Whole virus vaccines, recombinant protein subunit vaccines, and nucleic acid vaccines [8]. Different vaccines through different technology platforms, all aim to present either a weakened form of the SARS-CoV-2 or component of the virus to the immune system. The World Health Organisation (WHO) lists many candidate COVID-19 vaccines [9]. The majority work on the concept of direct immunity to the spike protein of SARS-CoV-2 virus. One particular strategy may be better than another for several reasons like cost, ease of manufacture and stability without refrigeration. This is particularly important for delivering vaccination programs to developing countries.

Does a SARS-CoV-2 vaccine generate an appropriate immune response?

Globally, multiple clinical trials are in progress with some promising results. Many vaccines using different approaches have now been shown to raise antibodies and T-cell responses in Phase I/II trials, but we won’t know if these are protective until vaccinated individuals are exposed to the virus. It’s not clear how long protective responses are effective. As the scientific community works to develop an effective vaccine, understanding natural immunity to COVID-19 will be important.

Is a natural SARS-CoV-2 infection protective and what about re-infection?

To look at what science is telling us, a systematic review was published where the authors reviewed 322 suitable studies to look at antibody mediated immunity to coronaviruses. Antibodies specific for SARS-CoV-2 were on average detected 11 days from the start of symptoms and these typically waned over time, being mostly detectable up to at least a year post the start of symptoms. Longer durations were usually associated with more severe symptoms. Human challenge studies with HCoV indicated that the detectable antibody levels did indicate protection from infection and disease. However, repeat human challenge experiments with single HCoV suggest individuals can be infected with the same HCoV one year after first challenge but with possible lower severity [10]. Natural infection with SARS-CoV-2 also generates cellular immunity with the induction of T lymphocytes. Successful vaccines aim to recreate the same immunity found from a natural infection. The good news is that first generation COVID-19 vaccines (which are mainly directed at the spike protein of SARS-CoV-2) have been found to elicit T cell responses which are similar to a natural infection. Data from looking at natural infection also show that other proteins are just as important as the spike protein (e.g. M, nsp6, ORF3a and N). Therefore, an optimal vaccine approach in the future may combine different targets to that of the SARS-CoV-2 spike protein [11].   

Will repeat vaccination be required?

As the world learns about COVID-19, it’s still too early to tell if one vaccination will provide lifelong immunity or if boosters will be required. This will depend on the ability to maintain high enough levels of cellular and antibody responses for individuals to be protected. To know this we need to follow up with individuals enrolled in clinical trials.

Challenges of reaching herd immunity?

At this point it’s clear to see that one of the biggest barriers to reaching herd immunity is going to be the politics and cost of distribution, the logistics such as storage and ease of administration. The general outlook shows governments buying the necessary vaccines. The hope of scientists is that people will put national allegiances and politics aside and use the vaccine that is proven to be the most scientifically robust. The easiest vaccine to manufacture or first product to market may not necessarily be the best at providing protection. 

Vaccine hesitancy could be another big barrier to herd immunity. Recent polls suggest that as few as 50% of people in the United States are willing to be vaccinated. To combat this the US Centers for Disease Control and Prevention (CDC) is now working to boost “vaccine confidence” [12].

While there are subsets of the population that are unsure about vaccination, it’s hard to ignore that vaccination is a success story. For instance, vaccination has been able to eradicate the polio and smallpox largely throughout the world, two severely debilitating diseases.

Conclusion

To get SARS-CoV-2 under control globally, vaccination programs are only one part of the equation. Many control measures will need to continue such as improving diagnostics, generating novel anti-virals, fully understanding optimal treatment regimens and continuing to moderate our behaviour in terms of social distancing and hygiene.  If SARS-CoV-2 vaccination can generate long last immunity and science is behind this strategy, in time herd immunity may just be possible, but it will require global collaboration and on-going research.

References

1. Delamater PL, Street EJ, Leslie TF, Yang YT, Jacobsen KH. Complexity of the Basic Reproduction Number (R0). Emerg Infect Dis. 2019;25(1):1-4. doi:10.3201/eid2501.171901

2. The world in lock down https://www.bbc.co.uk/news/world-52103747

3,http://venturesafrica.com/against-the-norm-countries-taking-no-lockdown-approach-to-covid-19/

4. General Sweden Strategy https://www.bbc.co.uk/news/world-europe-53498133 & Has Sweden’s controversial covid-19 strategy been successful? Heba Habib freelance journalist Cite this as: BMJ 2020;369:m2376. http://dx.doi.org/10.1136/bmj.m2376 Published: 12 June 2020

5. Randolph, H.E. Herd Immunity: Understanding COVID-19. Immunity 2020 May 19; 52 (5): 737-741.

6. BBC Word News 5th August Sir Jeremy Farrar https://www.bbc.co.uk/programmes/w3cszc6n

7. Operation Warp Speed – The White House https://www.whitehouse.gov/briefings-statements/president-trump-leading-generation-effort-ensure-americans-access-covid-19-vaccine/

8. Chen WH, Strych U, Hotez PJ, Bottazzi ME. The SARS-CoV-2 Vaccine Pipeline: an Overview [published online ahead of print, 2020 Mar 3]. Curr Trop Med Rep. 2020;1-4. doi:10.1007/s40475-020-00201-6

9. http://www.who.int/publications/m/item/draft-landscape-of-COVID-19-candidate-vaccines

10.  Angkana T. Huang 1,2*, Bernardo Garcia-Carreras1,2*, Matt D.T. Hitchings1,2*, Bingyi Yang1,2*,Leah C. Katzelnick1,2*, Susan M. Rattigan1,2, Brooke A. Borgert1,2, Carlos A. Moreno1,2,Benjamin D. Solomon3, Isabel Rodriguez-Barraquer4, Justin Lessler5, Henrik Salje6, Donald Burke7, Amy Wesolowski5, Derek A.T. Cummings1,2 medRxiv preprint doi: https://doi.org/10.1101/2020.04.14.20065771.this version posted April 17, 2020 A systematic review of antibody mediated immunity to coronaviruses: antibody kinetics, correlates of protection, and association of antibody responses with severity of disease

11. Grifoni A, Weiskopf D, Ramirez SI, et al. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell. 2020;181(7):1489-1501.e15. doi:10.1016/j.cell.2020.05.015

12. https://www.sciencemag.org/news/2020/06/just-50-americans-plan-get-covid-19-vaccine-here-s-how-win-over-rest