Kristin Davis, Research Assistant, CITF Secretariat
Bruce Mazer, Associate Scientific Director – Strategy, CITF Secretariat
With the arrival of Omicron and the looming threat of other variants to come, the question on everyone’s mind is: how long does immunity to SARS-CoV-2 last? Protection from SARS-CoV-2 infection and the disease it causes (COVID-19) cannot be fully understood without concrete “real-world” data on immunity and recurrence. Because SARS-CoV-2 is still a relatively new virus, the duration of immunity is a very active research question. Data are being collected and analyzed in real-time. CITF experts are among those grappling with this issue and we offer a current overview from around the world of where the science stands to date.
Immune memory: An overview
Recovery from a viral infection is typically followed by a period of immunological memory. After fighting the infection, antibody-producing B-cells enter a dormant state known as ‘memory’ B-cells. These linger in the body, patiently awaiting their next confrontation with the virus against which they were primed. T-cells also become dormant, remembering the viral intruder, ready to mount a swift immune response and directly kill virus-infected cells in any future encounters.
This is the basis underlying vaccination: the immune system is exposed to a harmless protein fragment of a virus. This activates an immune response to make antibodies and T-cells for future exposures to the virus.
Normally, if not called upon, antibodies fade over a period of months to years. Immunity acquired to some viruses, including influenza and the seasonal coronaviruses causing the common cold, also diminishes because the virus’ genetic evolution helps them evade pre-programmed immune responses (1-3). As a result, most immunization schedules include additional doses of vaccine, called boosters. As their name suggests, boosters, administered sometime after the first or ‘primer’ doses, help to stimulate the immune system through re-exposure. Memory B-cells and T-cells are called into action and fine-tune their immune responses in a manner that is more long-lasting. Hence, boosters help by elevating immunity to the same level as, or higher than, the first exposure.
Why do we need boosters for COVID-19?
Part one: Waning immunity
In the months since most Canadians received their last vaccine dose, immunity has most likely declined. Thus, they need re-exposure: a booster is the ideal way.
- Breakthrough infections more frequent months after vaccination
Research emerging from Israel comparing individuals 60 years and older who received a third shot of Pfizer-BioNTech’s Comirnaty vaccine to those who had received only two doses found that the third shot made people 11 times less likely to acquire a breakthrough infection and 20 times less likely to become severely ill from COVID-19 (4). Recent preprints (not yet peer-reviewed) have demonstrated that a third dose of an mRNA vaccine could significantly increase vaccine effectiveness against both the Delta and Omicron variants (5,6). These studies offer preliminary evidence indicating that a booster helps address waning immunity, especially against emerging variants.
- Antibody levels decline over time
Data are currently insufficient to define a measurable unit of immunity, known as a correlate of protection, that indicates whether an individual is protected from infection. However, we do know that the mean peak of neutralizing (that is to say, virus-blocking) antibody titers and anti-SARS-CoV-2 spike antibodies is strongly correlated with a lower risk of infection (7,8). Multiple studies supported by Canada’s COVID-19 Immunity Task Force (CITF) have shown that antibodies against SARS-CoV-2 diminish significantly with time since infection and/or vaccination (9-15).
Part two: Immune evasion
As genetic modifications help viruses evade built-up immunity, it is not surprising that highly mutated strains of SARS-CoV-2, such as Omicron, will cause more reinfections and breakthrough infections. Indeed, recent and not yet peer-reviewed studies have found reinfection rates to be at least three times higher with Omicron as compared to Delta (16,17). Not only has Omicron emerged at a time when swaths of the population had waning immunity to SARS-CoV-2, but its constellation of mutations has also allowed it to escape existing immunity.
An additional vaccine dose is more effective when faced with highly mutated variants
Two reports released in preprint from Australia and Israel have demonstrated that a third dose of the Pfizer-BioNTech vaccine significantly increases neutralizing antibodies recognizing the original strain of SARS-CoV-2, as well as the Delta and Omicron variants (18,19). Moreover, a growing body of evidence suggests that, while antibodies to the original strain of SARS-CoV-2 are less specific to variants, higher levels of these antibodies can still be effective in countering infection (20,21). Since boosters help to elevate the level of antibodies, including neutralizing antibodies, they are particularly helpful in the context of emerging variants. Therefore, the possibility of immune evasion is the second reason behind the pressing need for boosters in the Canadian population.
Further to this, CITF research has confirmed that virus-specific T-cells persist at least nine months after first exposure (21). In contrast to what we see with antibodies, T-cells may still easily recognize the heavily mutated Omicron SARS-CoV-2 virus (23,24).
CITF research on durability
The CITF supports several research projects striving to understand the duration of immunity to SARS-CoV-2. Studies of older Canadians (such as residents in long-term care homes) and of those at higher risk of illness due to underlying health conditions (such as those who are immunocompromised) have pivoted to monitor the added benefit of a third dose (25-27). Booster doses have been administered following recommendations from the National Advisory Committee on Immunization in October 2021 in these more vulnerable populations.
Additionally, the Canadian Immunization Research Network (CIRN) Provincial Collaborative Network (PCN), funded in part by the CITF, has released reports of the effectiveness of two vaccine doses against symptomatic SARS-CoV-2 infection and severe outcomes (28,29). Indeed, this network has already started to monitor the incidence and severity of breakthrough infections in the Omicron-fuelled era (6).
Beyond its multiple population-based studies, the CITF also supports several studies focused on immune science and testing. Information stemming from these studies has been instrumental in understanding the depth, breadth, and persistence of immune responses to COVID-19 infection and vaccination (14,15,22, 30-32).
The best protection against SARS-CoV-2 comes from vaccination. Being optimally protected includes receiving a booster when it becomes available – even for those previously infected – while continuing to follow local public health measures. With Omicron’s mutations and increased transmissibility, a booster has become essential, even in vaccinated and otherwise healthy adults. Despite our current vaccines having been developed with the original SARS-CoV-2 strain in mind, early studies from various parts of the world have all concluded that a booster provides additional protection against the highly mutated Omicron.
- Townsend JP, Hassler HB, Wang Z, Miura S, Singh J, Kumar S, et al. The durability of immunity against reinfection by SARS-CoV-2: a comparative evolutionary study. Lancet Microbe. 2021;2(12):e666-e75.
- Eguia RT, Crawford KHD, Stevens-Ayers T, Kelnhofer-Millevolte L, Greninger AL, Englund JA, et al. A human coronavirus evolves antigenically to escape antibody immunity. PLoS Pathog. 2021;17(4):e1009453.
- Edridge AWD, Kaczorowska J, Hoste ACR, Bakker M, Klein M, Loens K, et al. Seasonal coronavirus protective immunity is short-lasting. Nat Med. 2020;26(11):1691-3.
- Bar-On YM, Goldberg Y, Mandel M, Bodenheimer O, Freedman L, Kalkstein N, et al. Protection of BNT162b2 vaccine booster against Covid-19 in Israel. New England Journal of Medicine. 2021;385(15):1393-400.
- Andrews N, Stowe J, Kirsebom F, Toffa S, Rickeard T, Gallagher E, et al. Effectiveness of COVID-19 vaccines against the Omicron (B.1.1.529) variant of concern. medRxiv. 2021.
- Buchan SA, Chung H, Brown KA, Austin PC, Fell DB, Gubbay J, Nasreen S, Schwartz KL, Sundaram ME, Tadrous M, Wilson K, Wilson SE, Kwong J. Effectiveness of COVID-19 vaccines against Omicron or Delta infection. medRxiv. 2022.
- Khoury DS, Cromer D, Reynaldi A, Schlub TE, Wheatley AK, Juno JA, et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med. 2021;27(7):1205-11.
- Earle KA, Ambrosino DM, Fiore-Gartland A, Goldblatt D, Gilbert PB, Siber GR, et al. Evidence for antibody as a protective correlate for COVID-19 vaccines. Vaccine. 2021;39(32):4423-8.
- Brockman MA, Mwimanzi F, Lapointe HR, Sang Y, Agafitei O, Cheung P, et al. Reduced magnitude and durability of humoral immune responses to COVID-19 mRNA vaccines among older adults. J Infect Dis. 2021.
- Abe KT, Hu Q, Mozafarihashjin M, Samson R, Manguiat K, Robinson A, et al. Neutralizing antibody responses to SARS-CoV-2 variants in vaccinated Ontario long-term care home residents and workers. medRxiv. 2021.
- Yau K, Abe KT, Naimark D, Oliver MJ, Perl J, Leis JA, et al. Evaluation of the SARS-CoV-2 Antibody Response to the BNT162b2 Vaccine in Patients Undergoing Hemodialysis. JAMA Netw Open. 2021;4(9):e2123622.
- Grunau B, Asamoah-Boaheng M, Lavoie PM, Karim ME, Kirkham TL, Demers PA, et al. A Higher Antibody Response Is Generated With a 6- to 7-Week (vs Standard) Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine Dosing Interval. Clin Infect Dis. 2021.
- Grunau B, Goldfarb DM, Asamoah-Boaheng M, Golding L, Kirkham TL, Demers PA, et al. Immunogenicity of Extended mRNA SARS-CoV-2 Vaccine Dosing Intervals. JAMA. 2021.
- Perreault J, Tremblay T, Fournier MJ, Drouin M, Beaudoin-Bussières G, Prévost J, et al. Waning of SARS-CoV-2 RBD antibodies in longitudinal convalescent plasma samples within 4 months after symptom onset. Blood. 2020;136(22):2588-91.
- Anand SP, Prévost J, Nayrac M, Beaudoin-Bussières G, Benlarbi M, Gasser R, et al. Longitudinal analysis of humoral immunity against SARS-CoV-2 Spike in convalescent individuals up to 8 months post-symptom onset. bioRxiv. 2021.
- Pulliam JRC, van Schalkwyk C, Govender N, von Gottberg A, Cohen C, Groome MJ, et al. Increased risk of SARS-CoV-2 reinfection associated with emergence of the Omicron variant in South Africa. medRxiv. 2021.
- SARS-CoV-2 variants of concern and variants under investigation in England Technical briefing 31. UK Health Security Agency; 2021 Dec 10 [updated 2021 Dec 10, cited 2021 Dec 17]. Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1042367/technical_briefing-31-10-december-2021.pdf
- Basile K, Rockett RJ, McPhie K, Fennell M, Johnson-Mackinnon J, Agius JE, et al. Improved neutralization of the SARS-CoV-2 Omicron variant after Pfizer-BioNTech BNT162b2 COVID-19 vaccine boosting. bioRxiv. 2021.
- Nemet I, Kliker L, Lustig Y, Zuckerman NS, Erster O, Cohen C, et al. Third BNT162b2 vaccination neutralization of SARS-CoV-2 Omicron infection. N Engl J Med. 2021.
- Rössler A, Riepler L, Bante D, Laer Dv, Kimpel J. SARS-CoV-2 B.1.1.529 variant (Omicron) evades neutralization by sera from vaccinated and convalescent individuals. medRxiv. 2021.
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- Law JC, Girard M, Chao GYC, Ward LA, Isho B, Rathod B, et al. Persistence of T Cell and Antibody Responses to SARS-CoV-2 Up to 9 Months after Symptom Onset. J Immunol. 2021.
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- Madelon N, Heikkila N, Sabater Royo I, Fontannaz P, Breville G, Lauper K, et al. Omicron-specific cytotoxic T-cell responses are boosted following a third dose of mRNA COVID-19 vaccine in anti-CD20-treated multiple sclerosis patients. medRxiv. 2021.
- Zhang A, Breznik JA, Clare R, Nazy I, Miller MS, Bowdish DME, et al. Antibody Responses to 3rd Dose mRNA Vaccines in Nursing Home and Assisted Living Residents. medRxiv. 2021.
- Kumar D, Ferreira VH, Hall VG, Hu Q, Samson R, Ku T, et al. Neutralization of SARS-CoV-2 Variants in Transplant Recipients After Two and Three Doses of mRNA-1273 Vaccine : Secondary Analysis of a Randomized Trial. Ann Intern Med. 2021.
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- Chung H, He S, Nasreen S, Sundaram ME, Buchan SA, Wilson SE, et al. Effectiveness of BNT162b2 and mRNA-1273 covid-19 vaccines against symptomatic SARS-CoV-2 infection and severe covid-19 outcomes in Ontario, Canada: test negative design study. Bmj. 2021;374:n1943.
- Nasreen S, Chung H, He S, Brown KA, Gubbay JB, Buchan SA, et al. Effectiveness of mRNA and ChAdOx1 COVID-19 vaccines against symptomatic SARS-CoV-2 infection and severe outcomes with variants of concern in Ontario. medRxiv. 2021.
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- Anand SP, Prévost J, Richard J, Perreault J, Tremblay T, Drouin M, et al. High-throughput detection of antibodies targeting the SARS-CoV-2 Spike in longitudinal convalescent plasma samples. Transfusion. 2021;61(5):1377-82.