mRNAワクチンによるオミクロン防御が限定的である理由を説明できるかもしれない新しい知見(New findings may explain why mRNA vaccines provide limited protection against omicron)


2023-07-13 カロリンスカ研究所(KI)



粘膜IgAはBQ.1およびBQ.1.1感染を防御する Mucosal IgA protects against BQ.1 and BQ.1.1 infection

Ulrika Marking,Oscar Bladh,Sebastian Havervall,Nina Greilert-Norin,Max Gordon,Jessica J Alm,Kim Blom,Mikael Åberg,Jonas Klingström,Charlotte Thålin
The Lancet Infectious Diseases  Published:July 12, 2023

While SARS-CoV-2 vaccines and previous infections still safeguard against severe and fatal COVID-19, protection against infection has waned substantially after the emergence of the SARS-CoV-2 Omicron variants.1BQ.1 and sub-lineages (hereafter indicated as BQ.1*) evolved several mutations, including Arg346Thr (BQ.1.1), Lys444Thr (BQ.1*), and Asn460Lys (BQ.1*), leading to strong evasion of neutralising antibodies in serum samples from vaccinated and convalescent people.2

We recently showed that original SARS-CoV-2 spike-specific mucosal (nasal) IgA antibodies (hereafter mucosal IgA) are associated with protection against Omicron BA.1, BA.2, and BA.5 breakthrough infections.3, 4 To investigate if mucosal IgA and original SARS-CoV-2 spike-specific serum IgG (hereafter serum IgG) could also protect against infection with more recently emerged Omicron subvariants, we conducted a 15 week, once weekly, qPCR screening study from October 2022, to January 2023, in 447 health-care workers (appendix pp 4–5). Mucosal IgA and serum IgG responses were analysed at enrolment alongside the baseline qPCR sample (appendix pp 2–4).

Seven participants were qPCR positive for SARS-CoV-2 at baseline and included in estimation of cumulative incidence but excluded from all other analyses. In total, 89 participants (cumulative incidence: 20%) were qPCR positive during the screening period. The most common subvariants identified were BQ.1* (n=42), BA.5 (n=7), BF (n=5), and XBB (n=5; appendix p 6).

At baseline, mucosal IgA above cut-off (based on pre-pandemic samples, appendix p 3) were detected in 358 participants (81%), whereas all participants were above cut-off in serum IgG (appendix p 7). The risk of subsequent Omicron infection was significantly lower in participants with mucosal IgA above cut-off at baseline, with an incidence rate ratio (IRR) of 0·42 (95% CI 0·26–0·70 between participants with mucosal IgA above or below cut-off [by Poisson regression adjusted for age, sex, and baseline serum IgG levels]). Interestingly, a sub-analysis including only participants with detectable mucosal IgA at baseline, revealed a linear increase in protective effect per duplication of baseline mucosal IgA levels, with an IRR of 0·75 (95% CI 0·62–0·90; figure A; appendix p 7). A sub-analysis investigating only BQ.1* infections showed a similar protective effect, with an IRR of 0·24 (95% CI 0·12–0·47) for participants with detectable baseline mucosal IgA levels and an IRR of 0·62 [95% CI 0·46–0·82] per duplication of baseline mucosal IgA levels among participants with detectable baseline mucosal IgA (figure B; appendix p 7).

Figure thumbnail gr1

FigureMucosal IgA protection and cross-binding capacity

We next assessed the cross-binding capacity of serum IgG and mucosal IgA, by calculating the ratio between titres of specific variant and original SARS-CoV-2 antibodies. As expected, the highest cross-binding ratio was observed for BA.5 and lowest for XBB 2 (figure C). A high ratio of variant spike binding relative to original spike binding reduced the risk of infection with an IRR of 0·34 (95% CI 0·18–0·60) for BA.5 and 0·41 (95% CI 0·22–0·70) for BQ.1 (figure D).

We recently showed that the additional protection against infection conferred by the combination of infection and vaccine induced immunity is largely mediated by mucosal IgA. 5 In this cohort, when adjusted for mucosal IgA levels, serum IgG levels were not significantly associated to protection against SARS-CoV-2 Omicron infection (IRR 0·95 [95% CI 0·85–1·08] per duplication of serum IgG titre; figure A; appendix p 7). Additionally, a sub-analysis of the 82 participants without detectable baseline mucosal IgA (of whom 30 became infected) showed no association between serum IgG and protection against infection (IRR 1·03 [95% CI 0·88–1·24] per duplication of serum IgG titre).

This study is limited by the lack of live virus neutralisation analyses in serum and nasal secretions. However, binding of original SARS-CoV-2 spike-specific serum IgG correlates with serum BA.1 neutralising antibodies, 5 and binding antibodies have been shown to be associated to protection against infection with previous SARS-CoV-2 variants including the Delta and Omicron BA.1 and BA.2 variants. 5, 6

Although serum IgG levels were associated with protection against infection with previous SARS-CoV-2 variants,5 ,6 ,7, 8 our findings now question the use of serum IgG levels as correlates of protection against infection with recent Omicron variants. Instead, in an era with increasing viral immune evasiveness and high rates of previous infection, mucosal antibodies correlate stronger with protection against infection, probably due to the localisation at the viral point of entry alongside a broader cross-binding capacity.

SARS-CoV-2ワクチン4回接種後の粘膜免疫応答 Mucosal immune responses following a fourth SARS-CoV-2 vaccine dose

Oscar Bladh,Ulrika Marking,Sebastian Havervall,Nina Greilert Norin,Katherina Aguilera,Sophia Hober,Anna Smed-Sörensen,Max Gordon,Kim Blom,Mikael Åberg,Jonas Klingström,Charlotte Thålin
The Lancet Microbe  Published:April 19, 2023

We previously highlighted the importance of mucosal IgA, but not IgG, in preventing SARS-CoV-2 infection. 1 Although intramuscular SARS-CoV-2 vaccines might strengthen mucosal IgA antibody responses in previously infected individuals, 2 the effect on mucosal immune responses upon repeated booster doses is largely unknown. Here we investigated SARS-CoV-2 spike-specific IgA and IgG responses in the mucosa (nasal samples) and serum following booster mRNA vaccination (fourth dose) in individuals with and without previous SARS-CoV-2 infection.

Participants were enrolled via an ongoing prospective cohort study of health-care workers,1  with repeated serological measurements taken every four months since April, 2020. Serum and mucosal anti-spike antibodies were measured at 0, 3, 7, 14, and 30 days after booster mRNA vaccination (fourth dose) in 24 participants (appendix pp 6–7). Previous SARS-CoV-2 infection was confirmed with a positive qPCR test recorded in the national communicable diseases register or within the regular qPCR screening programs within the study protocol, a self-reported positive rapid diagnostic test, seroconversion at any follow-up visits before vaccination, or seroconversion to SARS-CoV-2 nucleocapsid antigen after vaccination.

Serum wild-type anti-spike IgG concentrations increased following the booster dose, as anticipated, both in participants without (n=5) and with (n=19) previous infection (appendix pp 8–10). Notably, anti-spike serum-IgA and nasal-IgA antibody concentrations against wild-type or BA.5 did not increase regardless of previous infection (appendix pp 8–12, 15). Nasal wild-type anti-spike IgA concentrations correlated strongly with nasal wild-type anti-spike secretory IgA concentrations, (correlation coefficient [r]=0·91, p<0·001; appendix p 13), but there was no correlation between the fold changes of nasal anti-spike IgA and serum anti-spike IgG (r=0·1, p=0·8; appendix p 14). Conversely, nasal wild-type anti-spike IgG increased in both SARS-CoV-2 naive participants (n=5) and previously infected participants (n=19; appendix pp 8–9) and fold change in nasal wild-type anti-spike IgG correlated strongly to serum wild-type anti-spike IgG (r=0·78, p<0·0001; appendix p 14), suggesting a passive transudation of plasma IgG into the mucosa.

Although a fourth vaccine dose provides increased protection against severe disease and death in frail individuals,3 protection against infection is restricted 4 and viral transmission is abundant also in populations with a high vaccine uptake. Our previous work shows a mucosal correlate of protectionmediated by nasal IgA acquired from previous infection.1, 5 Our current findings show that mucosal IgA responses are poorly boosted by systemic mRNA vaccines, also in immunocompetent individuals with previous infection, emphasising the need for alternative vaccine platforms enhancing mucosal immunity.

This study was supported by grants from the Jonas and Christina af Jochnick Foundation, Region Stockholm, SciLifeLab, the Knut and Alice Wallenberg Foundation, the Leif Lundblad Family Foundation, the Swedish Research Council, the Swedish Heart and Lung Foundation, the Bill & Melinda Gates Foundation, and the Center for Innovative Medicine. We declare no competing interests.