Infection-acquired immunity to SARS-CoV-2 is not as strong as vaccine-induced immunity

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

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 10^th, 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.

Vaccination produces:

• 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

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 10^th, 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.

References

1. Tenforde MW, Self WH, Gaglani M, Ginde AA, Douin DJ, Talbot HK, et al. Effectiveness of mRNA Vaccination in Preventing COVID-19–Associated Invasive Mechanical Ventilation and Death — United States, March 2021–January 2022. MMWR Morb Mortal Wkly Rep. 2022;71(12):459-65.
2. Cromer D, Juno JA, Khoury D, Reynaldi A, Wheatley AK, Kent SJ, et al. Prospects for durable immune control of SARS-CoV-2 and prevention of reinfection. Nature Reviews Immunology. 2021;21(6):395-404.
3. Post N, Eddy D, Huntley C, Van Schalkwyk MCI, Shrotri M, Leeman D, et al. Antibody response to SARS-CoV-2 infection in humans: A systematic review. PLOS ONE. 2020;15(12):e0244126.
4. Cervia C, Nilsson J, Zurbuchen Y, Valaperti A, Schreiner J, Wolfensberger A, et al. Systemic and mucosal antibody responses specific to SARS-CoV-2 during mild versus severe COVID-19. Journal of Allergy and Clinical Immunology. 2021;147(2):545-57.e9.
5. He Z, Ren L, Yang J, Guo L, Feng L, Ma C, et al. Seroprevalence and humoral immune durability of anti-SARS-CoV-2 antibodies in Wuhan, China: a longitudinal, population-level, cross-sectional study. Lancet. 2021;397(10279):1075-84.
6. Gudbjartsson DF, Norddahl GL, Melsted P, Gunnarsdottir K, Holm H, Eythorsson E, et al. Humoral Immune Response to SARS-CoV-2 in Iceland. N Engl J Med. 2020;383(18):1724-34.
7. Wang H, Yuan Y, Xiao M, Chen L, Zhao Y, Haiwei Z, et al. Dynamics of the SARS-CoV-2 antibody response up to 10 months after infection. Cell Mol Immunol. 2021;18(7):1832-4.
8. Röltgen K, Powell AE, Wirz OF, Stevens BA, Hogan CA, Najeeb J, et al. Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome. Sci Immunol. 2020;5(54):eabe0240.
9. Beaudoin-Bussières G, Laumaea A, Anand SP, Prévost J, Gasser R, Goyette G, et al. Decline of Humoral Responses against SARS-CoV-2 Spike in Convalescent Individuals. mBio. 2020;11(5):e02590-20.
10. Alfego D, Sullivan A, Poirier B, Williams J, Adcock D, Letovsky S. A population-based analysis of the longevity of SARS-CoV-2 antibody seropositivity in the United States. EClinicalMedicine. 2021;36:100902.
11. Dan JM, Mateus J, Kato Y, Hastie KM, Yu ED, Faliti CE, et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science. 2021;371(6529).
12. Wheatley AK, Juno JA, Wang JJ, Selva KJ, Reynaldi A, Tan HX, et al. Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19. Nat Commun. 2021;12(1):1162.
13. Lumley SF, Wei J, O’Donnell D, Stoesser NE, Matthews PC, Howarth A, et al. The Duration, Dynamics, and Determinants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibody Responses in Individual Healthcare Workers. Clin Infect Dis. 2021;73(3):e699-e709.
14. 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. Cell Reports Medicine. 2021;2(6):100290.
15. Cohen KW, Linderman SL, Moodie Z, Czartoski J, Lai L, Mantus G, et al. Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection with persisting antibody responses and memory B and T cells. medRxiv. 2021.
16. 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. 2022;208(2):429-43.
17. Nantel S, Bourdin B, Adams K, Carbonneau J, Rabezanahary H, Hamelin M-È, et al. Immunogenicity of Pfizer-BioNTech COVID-19 mRNA Primary Vaccination Series in Recovered Individuals Depends on Symptoms at Initial Infection. medRxiv. 2022:2022.03.29.22272714.
18. Wei J, Matthews PC, Stoesser N, Maddox T, Lorenzi L, Studley R, et al. Anti-spike antibody response to natural SARS-CoV-2 infection in the general population. Nat Commun. 2021;12(1):6250.
19. Roeker LE, Knorr DA, Pessin MS, Ramanathan LV, Thompson MC, Leslie LA, et al. Anti-SARS-CoV-2 antibody response in patients with chronic lymphocytic leukemia. Leukemia. 2020;34(11):3047-9.
20. Cattaneo C, Cancelli V, Imberti L, Dobbs K, Sottini A, Pagani C, et al. Production and persistence of specific antibodies in COVID-19 patients with hematologic malignancies: role of rituximab. Blood Cancer J. 2021;11(9):151-.
21. Dayam RM, Law JC, Goetgebuer RL, Chao GYC, Abe KT, Sutton M, et al. Accelerated waning of immunity to SARS-CoV-2 mRNA vaccines in patients with immune mediated inflammatory diseases. medRxiv. 2022:2022.01.26.22269856.
22. Hall VG, Ferreira VH, Ierullo M, Ku T, Marinelli T, Majchrzak-Kita B, et al. Humoral and cellular immune response and safety of two-dose SARS-CoV-2 mRNA-1273 vaccine in solid organ transplant recipients. Am J Transplant. 2021;21(12):3980-9.
23. 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.
24. Yau K, Chan CT, Abe KT, Jiang Y, Atiquzzaman M, Mullin SI, et al. Differences in mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech) SARS-CoV-2 vaccine immunogenicity among patients undergoing dialysis. Cmaj. 2022;194(8):E297-e305.
25. Oliver MJ, Thomas D, Balamchi S, Ip J, Naylor K, Dixon SN, et al. Vaccine Effectiveness Against SARS-CoV-2 Infection and Severe Outcomes in the Maintenance Dialysis Population in Ontario, Canada. J Am Soc Nephrol. 2022;33(4):839-49.
26. Shire ZJ, Reicherz F, Lawrence S, Sudan H, Golding L, Majdoubi A, et al. Antibody response to the BNT162b2 SARS-CoV-2 vaccine in paediatric patients with inflammatory bowel disease treated with anti-TNF therapy. Gut. 2021.
27. Wang Z, Schmidt F, Weisblum Y, Muecksch F, Barnes CO, Finkin S, et al. mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. Nature. 2021;592(7855):616-22.
28. Barouch DH, Stephenson KE, Sadoff J, Yu J, Chang A, Gebre M, et al. Durable Humoral and Cellular Immune Responses Following Ad26.COV2.S Vaccination for COVID-19. medRxiv : the preprint server for health sciences. 2021:2021.07.05.21259918.
29. Goel RR, Apostolidis SA, Painter MM, Mathew D, Pattekar A, Kuthuru O, et al. Distinct antibody and memory B cell responses in SARS-CoV-2 naïve and recovered individuals following mRNA vaccination. Sci Immunol. 2021;6(58).
30. Sokal A, Barba-Spaeth G, Fernández I, Broketa M, Azzaoui I, La Selle Ad, et al. Memory B cells control SARS-CoV-2 variants upon mRNA vaccination of naive and COVID-19 recovered individuals. bioRxiv; 2021.
31. Walsh EE, Frenck RW, Falsey AR, Kitchin N, Absalon J, Gurtman A, et al. Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. New England Journal of Medicine. 2020;383(25):2439-50.
32. Israel A, Shenhar Y, Green I, Merzon E, Golan-Cohen A, Schäffer AA, et al. Large-scale study of antibody titer decay following BNT162b2 mRNA vaccine or SARS-CoV-2 infection. medRxiv. 2021.
33. Breznik JA, Zhang A, Huynh A, Miller MS, Nazy I, Bowdish DME, et al. Antibody Responses 3-5 Months Post-Vaccination with mRNA-1273 or BNT163b2 in Nursing Home Residents. J Am Med Dir Assoc. 2021;22(12):2512-4.
34. Abu Jabal K, Ben-Amram H, Beiruti K, Batheesh Y, Sussan C, Zarka S, et al. Impact of age, ethnicity, sex and prior infection status on immunogenicity following a single dose of the BNT162b2 mRNA COVID-19 vaccine: real-world evidence from healthcare workers, Israel, December 2020 to January 2021. Euro Surveill. 2021;26(6).
35. Brodin P. Immune determinants of COVID-19 disease presentation and severity. Nat Med. 2021;27(1):28-33.
36. Canaday DH, Oyebanji OA, Keresztesy D, Payne M, Wilk D, Carias L, et al. Significant reduction in humoral immunity among healthcare workers and nursing home residents 6 months after COVID-19 BNT162b2 mRNA vaccination. medRxiv. 2021:2021.08.15.21262067.
37. Schmidt F, Muecksch F, Weisblum Y, Da Silva J, Bednarski E, Cho A, et al. Plasma Neutralization of the SARS-CoV-2 Omicron Variant. New England Journal of Medicine. 2022;386(6):599-601.
38. Tartof SY, Slezak JM, Fischer H, Hong V, Ackerson BK, Ranasinghe ON, et al. Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study. Lancet. 2021;398(10309):1407-16.
39. Tenforde MW, Self WH, Naioti EA, Ginde AA, Douin DJ, Olson SM, et al. Sustained Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Associated Hospitalizations Among Adults – United States, March-July 2021. MMWR Morb Mortal Wkly Rep. 2021;70(34):1156-62.
40. Sheward DJ, Kim C, Ehling RA, Pankow A, Castro Dopico X, Dyrdak R, et al. Neutralisation sensitivity of the SARS-CoV-2 omicron (B.1.1.529) variant: a cross-sectional study. Lancet Infect Dis. 2022.
41. Medigeshi GR, Batra G, Murugesan DR, Thiruvengadam R, Chattopadhyay S, Das B, et al. Sub-optimal neutralisation of omicron (B.1.1.529) variant by antibodies induced by vaccine alone or SARS-CoV-2 Infection plus vaccine (hybrid immunity) post 6-months. EBioMedicine. 2022;78:103938.
42. Haveri A, Ekström N, Solastie A, Virta C, Österlund P, Isosaari E, et al. Persistence of neutralizing antibodies a year after SARS-CoV-2 infection in humans. Eur J Immunol. 2021;51(12):3202-13.
43. Buchan SA, Chung H, Brown KA, Austin PC, Fell DB, Gubbay JB, et al. Effectiveness of COVID-19 vaccines against Omicron or Delta symptomatic infection and severe outcomes. 2022.
44. Levin EG, Lustig Y, Cohen C, Fluss R, Indenbaum V, Amit S, et al. Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months. New England Journal of Medicine. 2021;385(24):e84.
45. Romero-Olmedo AJ, Schulz AR, Hochstätter S, Das Gupta D, Virta I, Hirseland H, et al. Induction of robust cellular and humoral immunity against SARS-CoV-2 after a third dose of BNT162b2 vaccine in previously unresponsive older adults. Nature Microbiology. 2022;7(2):195-9.
46. Mwimanzi FM, Lapointe HR, Cheung PK, Sang Y, Yaseen F, Umviligihozo G, et al. Older Adults Mount Less Durable Humoral Responses to a Two-dose COVID-19 mRNA Vaccine Regimen, but Strong Initial Responses to a Third Dose. medRxiv. 2022.
47. Plumb ID. Effectiveness of COVID-19 mRNA Vaccination in Preventing COVID-19–Associated Hospitalization Among Adults with Previous SARS-CoV-2 Infection—United States, June 2021–February 2022. MMWR Morb Mortal Wkly Rep. 2022;71.
48. Brumme ZL, Mwimanzi F, Lapointe HR, Cheung P, Sang Y, Duncan MC, et al. Humoral immune responses to COVID-19 vaccination in people living with HIV receiving suppressive antiretroviral therapy. 2021.
49. Hall VG, Ferreira VH, Ku T, Ierullo M, Majchrzak-Kita B, Chaparro C, et al. Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients. New England Journal of Medicine. 2021;385(13):1244-6.
50. Oliver MJ, Thomas D, Balamchi S, Ip J, Naylor K, Dixon SN, et al. Vaccine Effectiveness Against SARS-CoV-2 Infection and Severe Outcomes in the Maintenance Dialysis Population in Ontario, Canada. Journal of the American Society of Nephrology. 2022:ASN.2021091262.
51. Dayam RM, Law JC, Goetgebuer RL, Chao GYC, Abe KT, Sutton M, et al. Antibody and T cell responses to SARS-CoV-2 mRNA vaccines during maintenance therapy for immune-mediated inflammatory diseases. medRxiv. 2022:2022.01.26.22269856.
52. Röltgen K, Nielsen SCA, Silva O, Younes SF, Zaslavsky M, Costales C, et al. Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination. Cell. 2022;185(6):1025-40.e14.
53. Rössler A, Riepler L, Bante D, von Laer D, Kimpel J. SARS-CoV-2 Omicron Variant Neutralization in Serum from Vaccinated and Convalescent Persons. New England Journal of Medicine. 2022.
54. Hall V, Foulkes S, Insalata F, Kirwan P, Saei A, Atti A, et al. Protection against SARS-CoV-2 after Covid-19 Vaccination and Previous Infection. N Engl J Med. 2022;386(13):1207-20.
55. Cerqueira-Silva T, Andrews JR, Boaventura VS, Ranzani OT, de Araújo Oliveira V, Paixão ES, et al. 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. Lancet Infect Dis. 2022.
56. 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. 2022.
57. Chemaitelly H, Ayoub HH, AlMukdad S, Coyle P, Tang P, Yassine HM, et al. Duration of mRNA vaccine protection against SARS-CoV-2 Omicron BA.1 and BA.2 subvariants in Qatar. medRxiv. 2022:2022.03.13.22272308.
58. Tauzin A, Gong SY, Beaudoin-Bussières G, Vézina D, Gasser R, Nault L, et al. Strong humoral immune responses against SARS-CoV-2 Spike after BNT162b2 mRNA vaccination with a 16-week interval between doses. Cell Host & Microbe. 2022;30(1):97-109.e5.