Acquired Immune Responses Varies Substantially

When innate immunity, the initial defense against infection, is working properly — as it does in most people infected with Sars-Cov-2 who develop mild or no symptoms of disease — the second stage, adaptive immunity, kicks in after a few days.  

Warning: even mild Covid-19 infections can make people sick for months.^[14]

Figure 1.  Innate immunity vs Adaptive immunity 

Adaptive response

The nature of acquired immune responses following natural infection varies substantially among pathogens:^[11]

• Measles (1) or smallpox (2) virus
• Results in lifelong protection from the re-acquisition and re-transmission of secondary infections
• Influenza (3), respiratory syncytial virus (RSV) (4)
• Confer imperfect or transient clinical and transmission-blocking immunity either via pathogen evolution or waning immunological memory
• Dengue (5) or a vaccine (e.g., RSV (6))
• Could result in more clinically severe secondary infections due to a phenomena  known as antibody-dependent enhancement (ADE)

Table 1. Past Seasons Flu Vaccine Effectiveness Estimates (CDC Data)

VE: Vaccine Effectiveness  CI: credible Interval

Partially Effective (or Imperfect) Vaccines

The immunity conferred by such vaccines:

• May not provide complete protection against reinfection and/or disease (7)
• May be inferior to that acquired following natural infection (8)

Nevertheless, imperfect vaccines that reduce both the clinical severity and transmissibility of subsequent infections (if they do occur) can still provide population-level disease protection (7, 9, 10).

Figure. 2 Immune enhancement of human viral disease (details)

Key Questions

Obviously, a vaccine should be used only when it will benefit a patient. Benefit takes into account both the drug's ability to produce the desired result (efficacy) and the type and likelihood of adverse effects (safety).

Can an effective Covid-19 vaccine be developed?

A key question is whether protection against severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) will happen by widespread deployment of an effective vaccine or by repeated waves of infection over the next few years until ∼60 to 70% of people develop immunity. 

Because the human population is naïve to SARS-CoV-2, the consequences of repeated epidemics will be unacceptably high mortality, severe economic disruption, and major adjustments to our way of life. Therefore, the benefit of developing an effective vaccine is very high, and even greater if it can be deployed in time to prevent repeated or continuous epidemics.

Figure 3.  In antibody-dependent enhancement, sub-optimal antibodies (the blue Y-shaped structures in the graphic) bind to both viruses and Fc gamma receptors (labeled FcγRII) expressed on immune cells promoting infection of these cells. (Source: Jmarchn - Own work)

Can it be suitable for wide scale immunization?

Could the Covid-19 vaccine behave similar to the dengue vaccine?^[18]

In 2016 a partially effective vaccine for dengue fever became commercially available in the Philippines and Indonesia.  It has been approved for use by Mexico, Brazil, El Salvador, Costa Rica, Singapore, Paraguay, much of Europe, and the United States.  Based on [17], it states that:

Yesterday Sanofi Pasteur, maker of Dengvaxia, a promising dengue vaccine, announced it was changing the labeling on the vaccine to limit its use to people who have had previous exposure to dengue virus.

Pioneering dengue researchers Scott Halstead, MD, and Philip K. Russell, MD, PhD, predicted this move nearly 2 years ago. They had seen results from Dengvaxia's trials showing evidence of antibody-dependent enhancement (ADE), a dengue phenomenon that makes repeat infections more severe and can cause severe illness after vaccination in those who haven't been previously exposed to the virus.

SARS-CoV-2, like other betacoronaviruses, may have Dengue-like ADE, or antibody-dependent enhancement of disease (see Fig. 3). For those who aren’t aware, some viruses, including betacoronaviruses, have a feature called ADE. There is also something called Original Antigenic Sin, which is the observation that the body prefers to produce antibodies based on previously-encountered strains of a virus over newly- encountered ones.

In ADE, antibodies from a previous infection become non-neutralizing due to mutations in the virus’s proteins. These non-neutralizing antibodies then act as trojan horses, allowing live, active virus to be pulled into macrophages through their Fc receptor pathways, allowing the virus to infect immune cells that it would not have been able to infect before. This has been known to happen with Dengue Fever; when someone gets sick with Dengue, recovers, and then contracts a different strain, they can get very, very ill.

References

1. B. M. Laksono, R. D. de Vries, S. McQuaid, W. P. Duprex, R. L. de Swart, Measles Virus Host Invasion and Pathogenesis. Viruses 8, 210 (2016). 
2. P. D. Ellner, Smallpox: Gone but not forgotten. Infection 26, 263–269 (1998).
3. J. Dushoff, J. B. Plotkin, S. A. Levin, D. J. D. Earn, Dynamical resonance can account for seasonality of influenza epidemics. Proc. Natl. Acad. Sci. U.S.A. 101, 16915–16916 (2004).
4. V. E. Pitzer, C. Viboud, W. J. Alonso, T. Wilcox, C. J. Metcalf, C. A. Steiner, A. K. Haynes, B. T. Grenfell,Environmental drivers of the spatiotemporal dynamics of respiratory syncytial virus in the United States.PLOS Pathog. 11, e1004591 (2015).
5. N. Ferguson, R. Anderson, S. Gupta, The effect of antibody-dependent enhancement on the transmission dynamics and persistence of multiple-strain pathogens. Proc. Natl. Acad. Sci. U.S.A. 96, 790–794 (1999).
6. B. S. Graham, Rapid COVID-19 vaccine development. Science 368, 945–946 (2020).
7. S. Gandon, M. J. Mackinnon, S. Nee, A. F. Read, Imperfect vaccines and the evolution of pathogen virulence. Nature 414, 751–756 (2001). 
8. G. Anichini, C. Gandolfo, S. Fabrizi, G. B. Miceli, C. Terrosi, G. Gori Savellini, S. Prathyumnan, D. Orsi, G.Battista, M. G. Cusi, Seroprevalence to Measles Virus after Vaccination or Natural Infection in an Adult Population, in Italy. Vaccines 8, 66 (2020).
9. N. Arinaminpathy, I. K. Kim, P. Gargiullo, M. Haber, I. M. Foppa, M. Gambhir, J. Bresee, Estimating Direct and Indirect Protective Effect of Influenza Vaccination in the United States. Am. J. Epidemiol. 186, 92–100(2017). 
10. T. A. Perkins, R. C. Reiner Jr., G. España, Q. A. Ten Bosch, A. Verma, K. A. Liebman, V. A. Paz-Soldan, J. P.Elder, A. C. Morrison, S. T. Stoddard, U. Kitron, G. M. Vazquez-Prokopec, T. W. Scott, D. L. Smith, An agent-based model of dengue virus transmission shows how uncertainty about breakthrough infections influences vaccination impact projections. PLOS Comput. Biol. 15, e1006710 (2019).
11. Immune life history, vaccination, and the dynamics of SARS-CoV-2 over the next 5 years
12. Past Seasons Vaccine Effectiveness Estimates
13. Dengue Vaccine (Wikipedia)
14. Even mild Covid-19 infections can make People sick for months (Bloomberg)
15. Distinct Early Serological Signatures Track with SARS-CoV-2 Survival
16. Covid19 and the immune system — the good, the bad and the ugly 
17. Sanofi restricts dengue vaccine but downplays antibody enhancement
18. Spartacus COVID Letter