Neutralization of Omicron subvariants BA.1 and BA.5 by a booster dose of COVID-19 mRNA vaccine in a Japanese nursing home cohort

Abstract

The sustained epidemic of Omicron subvariants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide concern, and older adults are at high risk. We conducted a prospective cohort study to assess the immunogenicity of COVID-19 mRNA vaccines (BNT162b2 or mRNA-1273) in nursing home residents and staff between May 2021 and December 2022. A total of 335 SARS-CoV-2 naïve individuals, including 141 residents (median age: 88 years) and 194 staff (median age: 44 years) participated. Receptor-binding domain (RBD) and nucleocapsid (N) protein IgG and neutralizing titer (NT) against the Wuhan strain, Alpha and Delta variants, and Omicron BA.1 and BA.5 subvariants were measured in serum samples drawn from participants after the second and third doses of mRNA vaccine using SARS-CoV-2 pseudotyped virus. Breakthrough infection (BTI) was confirmed by a notification of COVID-19 or a positive anti-N IgG result in serum after mRNA vaccination. Fifty-one participants experienced SARS-CoV-2 BTI during the study period. The RBD IgG and NTs against Omicron BA.1 and BA.5 were markedly increased in SARS CoV-2 naïve participants 2 months after the third dose of mRNA vaccine, compared to those 5 months after the second dose, and declined 5 months after the third dose. The decline in RBD IgG and NT against Omicron BA.1 and BA.5 in SARS-CoV-2 naïve participants after the second and the third dose was particularly marked in those aged ≥ 80 years. BTIs during the BA.5 epidemic period, which occurred between 2 and 5 months after the third dose, induced a robust NT against BA.5 even five months after the booster dose vaccination. Further studies are required to assess the sustainability of NTs elicited by Omicron-containing bivalent mRNA booster vaccine in older adults.

Keywords: COVID-19; Neutralizing antibody; Older adults; Omicron subvariants; Pseudotyped virus; mRNA vaccine.

Fig. 1

Genomic epidemiology and study design. (A) Genomic epidemiology of SARS-CoV-2 variants or Omicron subvariants in Toyama Prefecture. The proportions of each variant or Omicron subvariant were determined by analyzing 0 to 178 SARS-CoV-2 positive samples in each month. (B) Flow chart of the nursing home cohort study. After the enrollment of 335 SARS CoV-2 naïve participants, participants with BTI were detected during epidemic periods of Alpha variant (n = 1), BA.1 subvariant (n = 14) and BA.5 subvariant (n = 36). Six participants had positive results for anti-N IgG 2 months (n = 2) and 5 months (n = 4) after the third dose. Seventy-seven study participants were excluded from the study because 49 received a fourth dose of mRNA vaccine before blood collection 5 months after the third dose. Fourteen staff members and seven residents declined blood collection 5 months after the third dose of mRNA vaccine, and seven residents died of old age. Abbreviations: V2, 1st and 2nd dose of vaccine; V3, 3rd dose of vaccine, V2 + 2 M, 2 months after the 2nd dose of vaccine; V2 + 5 M, 5 months after the 2nd dose of vaccine; V3 + 2 M, 2 months after the 3rd dose of vaccine; V3 + 5 M, 5 months after the 3rd dose of vaccine, BTI; breakthrough infection.

Fig. 2

Anti-RBD IgG titers and neutralizing titers at 2 and 5 months after two doses and the third dose of mRNA vaccine in participants with or without BTI. (A) SARS-CoV-2 RBD IgG antibody titers, (B) Neutralizing titers against SARS-CoV-2pv of SARS-CoV-2 naïve participants. (C) SARS-CoV-2 RBD IgG antibody titers, (D) Neutralizing titers of participants with BTI during BA.1 epidemic period (January to March 2022). (E) SARS-CoV-2 RBD IgG antibody titers, (F) Neutralizing titers of participants with BTI during BA.5 epidemic period (June to September 2022). 14 participants were infected from January to March 2022 (during the Omicron BA.1 epidemic period); and 36 participants were infected from June to September 2022 (during the Omicron BA.5 epidemic period). ^***, p < 0.001; ^**, p < 0.01; *, p < 0.05; NS, not significant. Abbreviations: RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; V2, 2nd dose of vaccine; V2 + 2 M, 2 months after the 2nd dose of vaccine; V2 + 5 M, 5 months after the 2nd dose of vaccine; V3, 3rd dose of vaccine; V3 + 2 M, 2 months after the 3rd dose of vaccine; V3 + 5 M, 5 months after the 3rd dose of vaccine; BTI, breakthrough infection.

Fig. 3

Anti-RBD IgG titers and neutralizing titers 2 and 5 months after two and three doses of mRNA vaccine in SARS-CoV2 naïve participants by age group. (A) SARS-CoV-2 RBD IgG titer. (B) Neutralizing titers against SARS-CoV-2pv. N = 284. ^***, p < 0.001; *, p < 0.05; NS, not significant, using the Jonckheere-Terpstra test. Abbreviations: RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SARS-CoV-2pv, severe acute respiratory syndrome coronavirus 2 pseudotyped virus.