As the COVID-19 pandemic evolves and new variants of SARS-CoV-2 emerge, incidents of breakthrough infections among vaccinated individuals and reinfections among previously infected individuals have risen worldwide. Now, as restrictions are lifted, it is important to understand the impact of vaccination – in conjunction with infection (hybrid immunity) – and of infection alone, to better inform public policy and recommendations for Canadians. Here, we summarize recent studies. The takeaway message: vaccination – with all recommended doses – is advised, even in individuals who have previously had COVID-19.
Researchers studying populations around the world have demonstrated that vaccination provides effective protection against severe outcomes associated with reinfection among individuals who had previously had SARS-CoV-2. This has become even more true with the advent of the Omicron variant, as infection-acquired immunity to this variant has so far been shown to be short-lived. Given the high transmissibility of Omicron, the public health focus continues to be on reducing the severity of disease outcomes and avoiding deaths.
Research has shown that prior infection alone does not confer sufficient immunity to ward off COVID-19. For those who have been vaccinated, but suffer a breakthrough infection, the resulting hybrid immunity may be more robust than that which is provided by vaccination alone. However, this is not to suggest that becoming infected is desirable. Precautions against COVID-19 are in everyone’s best interest to avoid serious illness and death, to thwart after-effects of the disease such as long COVID, and to prevent spreading the virus to others – including the most vulnerable and our loved ones.
The Omicron problem
The scope of Omicron infection has been so widespread that some people have become complacent about their prospect of getting infected, believing that it is, in effect, inevitable. However, infection from one strain of SARS-CoV-2 is not necessarily protective against other strains. Antibodies induced post-infection from prior strains (original strain or wild type, Alpha and Delta) are unable to fully block or neutralize Omicron strains (BA.1 and BA.2) (1). Furthermore, infection with Omicron alone does not induce a robust immune response and generates a very low level of antibodies. This makes one susceptible to reinfections with Omicron or with strains yet to emerge (1, 2). Vaccination with two or more doses (either before or after an infection with any strain of SARS-CoV-2), on the other hand, is associated with a robust and well-rounded immune response that is broadly effective against all variants, including Omicron, when measured against severe disease and death.
A large database cohort study from Brazil, recently published in The Lancet Infectious Diseases, evaluated the effectiveness of vaccines from Pfizer-BioNTech, Oxford-AstraZeneca, Johnson & Johnson Janssen, and Sinovac-CoronaVac in preventing reinfection and severe disease among people who had already experienced COVID-19 (3). The study demonstrated that all four vaccines were only moderately effective against symptomatic reinfection, but that all conferred significant benefits of protection against hospitalization or death (Pfizer: 89.7%; AstraZeneca: 89.9%; Johnson and Johnson: 57.7%; Sinovac: 81.3%) compared to unvaccinated individuals with a previous SARS-CoV-2 infection.
This is consistent with a Swedish study, in which researchers evaluated the effectiveness of hybrid immunity compared to immunity from a previous infection alone (4). They found that hybrid immunity (in this case two doses + a previous infection) offered a 90% lower risk of severe outcomes compared to infection-acquired immunity alone. The research team concluded that while the risk of reinfection and hospitalization could be low in individuals who had recovered from COVID-19, vaccination was associated with added protection and for a longer duration (it gave 9 extra months of protection) compared to infection alone.
A recent preprint evaluated the impact of infection-acquired, vaccine-induced, and hybrid immunity against symptomatic and severe COVID-19 caused by Omicron (BA.1 and BA.2) in Qatar (1). The researchers demonstrated that:
- Three doses of an mRNA vaccine were more effective than two against infection from BA.1 or BA.2;
- Hybrid immunity was highly effective (over 90%) against hospitalization and/or death caused by BA.1 or BA.2;
- Hybrid immunity with two or three doses of an mRNA vaccine and a prior infection was associated with the highest degree of protection against symptomatic infection.
All this data strongly suggest that vaccination, regardless of previous infection, is highly effective in preventing severe disease including when infection is caused by variants such as Omicron BA.1 and BA.2.
A recent study published in Cell employed a different methodology to compare the immune response from hybrid immunity with vaccine-induced immunity alone. While the critical correlates of protection against severe COVID-19 disease are still under investigation, the team evaluated the immunological markers of vaccination in both previously infected (hybrid immunity) and uninfected individuals (5). They collected plasma and peripheral blood mononuclear cells (PBMCs) from 24 uninfected people and 30 previously infected people. They demonstrated that:
- Hybrid immunity conferred a greater and more durable immune response, as indicated by RBD-specific memory B cells and neutralizing antibodies against SARS-CoV-2 (wild type, Beta, Delta and Omicron). This was compared to those who had received two doses of vaccine and had not been infected.
- Peak antibody levels in the previously uninfected group could be boosted by a third dose.
- Two doses of vaccine induced robust and durable T cell responses independent of prior infection, and that this did not further improve with a third dose.
- Prior infection induced a functionally distinct T cell response with a unique CD4+ T cell profile that was not observed in the response to either two or three doses of vaccination alone.
Altogether, this study demonstrated that more robust protection conferred by hybrid immunity can be attributed to specific humoral and cell-mediated immunological mechanisms.
Overall, these studies demonstrate that a combination of vaccine-acquired and infection-induced immunity confers the strongest and longest lasting immunity – certainly compared to prior infection alone. However, this does not suggest getting infected is a strategic way to boost immunity. It is abundantly clear that SARS-CoV-2 infection carries a serious risk of hospitalization or death (even otherwise healthy people have ended up in hospital and have died), of long-term consequences such as long COVID (the effects of which are still not clear), and of transmission to others (including vulnerable members of society and family).
Additionally, there is no guarantee that infection will induce immunity. Data presented in a CITF-funded study published in the Pediatric Infectious Disease Journal found that approximately 1 in 8 individuals with COVID-19 did not develop antibodies detectable in blood (a process known as seroconversion) as a result of infection (6). The chance of seroconversion was even lower among children (especially the youngest). Additionally, the predominant circulating strains of Omicron have been shown to be very weak at inducing long-term protection against any SARS-CoV-2 variant (1, 2).
Dependence on infection-acquired immunity is not a viable or appropriate strategy for protecting oneself against COVID-19. Vaccination with three or more doses is highly effective against severe infection and death. For vaccinated people who experience a breakthrough infection, the subsequent protection conferred may offer some advantages against future infections, but the important thing to note about this hybrid immunity is that it depends upon a person being fully vaccinated.
- Altarawneh HN, Chemaitelly H, Ayoub HH, Tang P, Hasan MR, Yassine HM, et al. Effect of prior infection, vaccination, and hybrid immunity against symptomatic BA.1 and BA.2 Omicron infections and severe COVID-19 in Qatar [Internet]. medRxiv; 2022 [cited 2022 May 24]. p. 2022.03.22.22272745. Available from: https://www.medrxiv.org/content/10.1101/2022.03.22.22272745v1
- Turelli P, Zaballa ME, Raclot C, Fenwick C, Kaiser L, Eckerle I, et al. Omicron infection induces low-level, narrow-range SARS-CoV-2 neutralizing activity [Internet]. medRxiv; 2022 [cited 2022 Jun 2]. p. 2022.05.02.22274436. Available from: https://www.medrxiv.org/content/10.1101/2022.05.02.22274436v1
- Effectiveness of CoronaVac, ChAdOx1 nCoV-19, BNT162b2, and Ad26.COV2.S among individuals with previous SARS-CoV-2 infection in Brazil: a test-negative, case-control study – PMC [Internet]. [cited 2022 May 24]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971277/
- Nordström P, Ballin M, Nordström A. Risk of SARS-CoV-2 reinfection and COVID-19 hospitalisation in individuals with natural and hybrid immunity: a retrospective, total population cohort study in Sweden. Lancet Infect Dis [Internet]. 2022 Apr 1 [cited 2022 May 24]; Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971363/
- Rodda LB, Morawski PA, Pruner KB, Fahning ML, Howard CA, Franko N, et al. Imprinted SARS-CoV-2-specific memory lymphocytes define hybrid immunity. Cell. 2022 Apr 28;185(9):1588-1601.e14.
- Bhatt M, Zemek RL, Tang K, Malley R, Plint AC, Pham-Huy A, et al. Antibody Seronegativity in COVID-19 RT-PCR–Positive Children. Pediatr Infect Dis J. :10.1097/INF.0000000000003573.