As of April 26, 2022, more than 3.7 million SARS-CoV-2 infections and approximately 38,847 COVID-19-related deaths have been reported in Canada. The National Advisory Committee on Immunization (NACI) recommends COVID-19 vaccinations for all Canadians over the age of 5, including those who have been previously infected. More than 31 million Canadians have received two doses of vaccine and, of those, more than 17 million have received a third dose. Since the emergence of the extremely transmissible Omicron variant, including its BA.2 and XE subvariants which have caused a significant jump in infections, more and more people will have “hybrid immunity” – a combination of infection- and vaccine-induced immunity. The rise in infections may also leave some convinced that infection-acquired immunity may be enough to confer protection. It is therefore imperative to have a better understanding of the differences between infection-acquired and vaccine-acquired immunity.
Immunity from infection is different than from vaccination
Data drawn from various studies strongly suggest that infection-acquired immunity is not a sufficient substitute for vaccination, supporting the need for everyone to be fully vaccinated (meaning third/fourth doses when eligible), including those who have recovered from previous infections. The consequences for those who become infected without being vaccinated appear to be far more severe than for individuals who are fully vaccinated: in Canada, the unvaccinated have a 4-5 times higher rate of hospitalization and death from COVID-19.
Because immunity wanes over time and new, more transmissible variants of concern have emerged over the course of the pandemic, reinforcing the immune system has proven necessary, and importantly, effective. A prime example: adults who received a booster or third dose of vaccine saw a 94% reduction in COVID-19-related severe outcomes and death during the Omicron era (1).
The evidence shows that those who have been vaccinated are, therefore, better protected against severe illness will fare best against COVID-19.
What we know about infection-acquired immunity
SARS-CoV-2 infection induces a robust humoral (antibodies against spike (S), receptor-binding domain (RBD) and nucleocapsid (N) regions of the SARS-CoV-2 virus) and cellular immune response (2-4). These antibodies wane naturally over time although anti-N antibodies appear to wane fastest, followed by anti-RBD and anti-S antibodies (5).
SARS-CoV-2-specific antibodies are detectable at the mucosal sites (in the nose and throat) and in the serum of infected individuals (4). Multiple studies report that at least 90% of individuals who contract COVID-19 develop anti-SARS-CoV-2 antibodies (6, 7). IgA, and IgG antibodies can be detected with a blood test 5 to 15 days following symptom onset (3, 8).
Some of the more important points to consider about infection-acquired immunity:
- IgA antibodies, developed at the mucosal sites decrease rapidly after infection:
- One study notes significant waning 1 month after a SARS-CoV-2 infection (9);
- Another study found a return to undetectable levels within 3 months following infection (8).
- IgG antibodies are more durable and remain detectable in approximately 90% of individuals up to 10 to 12 months post-infection (5, 10).
- Neutralizing antibodies appear to wane around 2 to 3 months following onset of infection and by 6 months they were observed to be below the limit of detection (11-14).
- Antibody-producing B cells increase in the first month and remain high for at least 8 months post-infection (11, 12, 14, 15).
- SARS-CoV-2 also induces cell-mediated immunity by activating SARS-CoV-2 specific CD4 and cytotoxic T cells which may last at least 7 months post infection (11, 12, 16).
Durability of protection due to infection-acquired immunity in healthy adults
|Immune marker||Durability of protection|
|IgA||Waning 1 month after infection (8)
Undetectable levels 3 months after infection (7)
|IgG||Detectable in 90% of people 10-12 months post-infection (4,9)
Waning can be seen 3-6 months post-infection (10)
|Neutralizing||Waning starts 2-3 months post-infection
Undetectable by 6 months post-infection (10-13)
|B cells||Increase in 1st month post-infection
Remain high for at least 8 months post-infection (10-12, 14)
|CD4, T cells||May last at least 7 months post-infection (11-12, 15)|
Infection-acquired immunity is not one size fits all
While most people exposed to SARS-CoV-2 mount immune responses, some may not – or their immune response may vary substantially. Some factors include:
- People with symptomatic SARS-CoV-2 infection tend to have higher antibody titers than those who are asymptomatic, and hospitalized people tend to have higher antibody levels (5, 6, 8, 13, 17).
- Both binding antibodies and neutralizing antibody titers rise faster and reach a higher peak in people with more severe COVID-19 (6, 8, 12). For at least 2–3 months following infection, those with moderate-to-severe COVID-19 illness have higher titers than people with mild illness (8, 12); these differences may persist for 5–8 months following infection (11, 13).
- Older age has been associated with a decreased likelihood of mounting an immune response (18), but high peak antibody levels are observed among those who do mount an immune response (6, 11, 13, 18).
- Other groups that face challenges in mounting an immune response after infection are people with blood cancers or who are receiving certain immunosuppressive medications (19, 20).
- Data on other medical conditions are more variable and are often confounded by the increased risk of severe disease associated with some comorbidities.
- Several CITF-funded studies of populations that are particularly vulnerable because they are immune-compromised due to illness (e.g. inflammatory bowel disease or other autoimmune disorders) or treatment for other illnesses (e.g., solid organ transplant recipients, cancer) underscored a variable response towards infection, which caused more severe disease but not necessarily more immune protection (21-26).
The power of vaccine-induced immunity with an initial dosing series
As of April 10th, 2022, up to 85.68% of Canadians aged 5 and above were fully vaccinated with an mRNA (Pfizer or Moderna) or vector-based (AstraZeneca) vaccine, or a mix-and-match combination of vaccines.
- anti-S and anti-RBD binding and neutralizing antibodies, which circulate in the blood and induce long-lasting memory B- and T-cell responses (27-30).
- a more consistent and higher-titer initial antibody response than from infection, particularly after two or more doses (31, 32).
- anti-S, anti-RBD and neutralizing antibodies that remain detectable at least 6–8 months following vaccination (28, 29).
- CD4+ and CD8+ T cells that continue to be relatively stable up to 6–8 months following vaccination (28, 29).
- a protective effect supported by longer-term components of the humoral response, including memory B cells (28, 30).
Durability of protection due to vaccine-induced immunity in healthy adults
|Immune marker||Durability of protection|
|Anti-S||Remains detectable at least 6–8 months following vaccination (28, 29)|
|Anti-RBD||Remains detectable at least 6–8 months following vaccination (28, 29)|
|Neutralizing antibodies||Remain detectable at least 6–8 months following vaccination (28, 29)|
|B cells||The protective effect of vaccine-induced immunity is also supported by longer-term components of the humoral response (28, 30)|
|CD4+, CD8+, T cells||Continues to be relatively stable up to 6–8 months following vaccination (28, 29)|
The immune responses may be reduced in older, immunosuppressed patients, and those with underlying chronic ailments (33). Studies have also found that people above the age of 65 have significantly lower peak anti-S and neutralizing antibody titers following vaccination than those who are younger (34). Age, comorbidities, and the presence of chronic diseases are responsible for the faster decay of both binding and neutralizing antibodies (35, 36).
Impact of variants on infection- and vaccine-induced immunity
Recent evidence has suggested that people infected with the original strain of SARS-CoV-2 have less protection against the Delta and Omicron variants (37). However, vaccination offers good protection against hospitalization or severe disease and death from these VOCs (38, 39). That said, neutralizing antibody responses after either infection or vaccination were substantially less effective against Omicron subvariants BA.1 and BA.2 than against the original SARS-CoV-2 (7-fold to 42-fold reduction). This might explain immune escape/vaccine breakthroughs or an overall decrease of vaccine effectiveness against infection in both COVID-19 recovered and vaccinated individuals (40-42).
Third doses are important
Recent evidence suggests that vaccine effectiveness is reduced over time. Significant waning of antibodies has been noted 6 months post-second vaccine dose (43, 44). In light of this evidence, a campaign for third vaccine doses was initiated in Canada and many other countries. Just over 54% of people 12 years of age or older had received a third vaccine dose by April 10th, 2022 in Canada.
Notable reasons for this third dose include:
- in a healthy (general) population, a third dose is highly protective against severe outcomes from Omicron (95%) (43).
- it induces a robust cellular and humoral immunity against SARS-CoV-2 in individuals (>80 years) that were previously non-responders towards a primary vaccination series (45).
- long-term care residents who received boosters before the Omicron wave were protected from the ravages experienced during the first wave of COVID-19 (46).
- estimated vaccine effectiveness against reinfections, that lead to hospitalization was approximately 68% after a third dose during the period predominated by the Omicron variant (47).
- Third doses were highly protective against recent SARS-CoV-2 variants in people living with HIV (48), cancer patients (CITF CanPath studies), solid organ transplant recipients (49), kidney transplant patients on dialysis (50), and other immunocompromised populations (51).
Is a fourth dose needed?
Whether due to age or chronic health conditions, there is growing evidence that a fourth dose might be needed to sustain protection from SARS-CoV-2 and its newly emerging variants in select populations. Different jurisdictions in Canada are already advocating a fourth dose for older individuals (i.e. in Quebec for anyone older than 60, in British Columbia and Manitoba for anyone over 70), the immune-compromised, and for some socio-economic groups who are especially vulnerable (i.e. First Nations People at various ages across the country). More research and time are needed to ascertain whether a fourth dose would be required or advisable for all populations.
Hybrid immunity builds with infections and vaccinations
With more Canadians getting COVID, hybrid immunity due to both infection AND vaccination is likely becoming the new norm. Serum from vaccinated individuals induced much lower neutralization against Omicron. However, serum from patients with hybrid immunity (COVID recovered + vaccinated or vaccinated + COVID recovered) was able to neutralize the Omicron variant, although to a much lesser degree than Delta or other variants (52, 53). Studies have shown that Omicron infection alone gives no protection against older VOCs (i.e., Alpha, Beta, Gamma and Delta variants) (54). Evidence has also shown that people who recovered from COVID-19 receive long-lasting benefits from a full course of vaccination (54-56):
- Hybrid immunity appears to be long-lasting and confers highly effective protection against symptomatic Omicron infections for at least 6-8 weeks after the last vaccine dose (54).
- People with two vaccine doses and a prior infection had a further 66% lower risk of re-infection than those with just infection-acquired immunity (56).
- Three vaccine doses in previously infected individuals offered 77% vaccine effectiveness against infection with the BA.2 Omicron subvariant (57).
- Previously infected individuals had a slower decline in antibody levels after vaccination than people who had been vaccinated but never infected or infected and never vaccinated (58).
- The risk of SARS-CoV-2 reinfection and COVID-19 hospitalization in individuals who survived and recovered from a previous infection remained low for up to 20 months. Vaccination seemed to further decrease the risk of reinfection or hospitalization for up to 9 additional months (56).
Further research is ongoing
A lot of unanswered questions remain as the pandemic evolves. Ongoing research studies funded by the CITF are examining some of these unresolved questions about immunity to SARS-CoV-2:
- Why do some immunocompromised populations (including people with HIV on optimal therapy with normal T-cell numbers; children with inflammatory bowel disease on maintenance therapies; individuals on maintenance treatment for solid organ malignancies) have a normal response to vaccines while others (solid organ transplant recipients; those with chronic renal failure and dialysis; those on therapies for cancer and autoimmunity that target antibody-producing B-cells or other immune suppressants) do not?
- Does Omicron infection impact the immune system differently than infection with other variants?
- What are the conditions that would lead to a recommendation that all Canadians need a fourth dose of vaccine?
- Would protection conferred by hybrid immunity change with newly emerging variants of concern?
During the winter of 2022, as the fifth wave of the pandemic fueled by Omicron crested across Canada and COVID-19 fatigue and frustration became more widespread, the notion that vaccination may not be necessary for those who have already been infected with SARS-CoV-2 gained popularity (56). Thus, many may have deferred getting fully vaccinated or boosting their immunity with a third or fourth dose on the presumption that having been infected gave them sufficient immunity. While each exposure to the virus and vaccination increases antibody levels, as of now, vaccination still remains the key mechanism to mount a robust palette of immune responses. Furthermore, exposure to the virus without the protection afforded by vaccines risks severe outcomes, including death. Thus, any immune advantage from having been infected is enhanced in combination with full vaccination.
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