Bivalent COVID-19 mRNA vaccine against omicron subvariants in immunocompromised patients.

Despite the end of the global COVID-19 public health emergency, SARS-CoV-2 infection continues to result in moderate to severe disease in immunocompromised patients.1Overvad M Koch A Jespersen B et al.Outcomes following SARS-CoV-2 infection in individuals with and without solid organ transplantation—Danish nationwide cohort study.Am J Transplant. 2022; 22: 2627-2636Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar Omicron variants (eg, BQ.1.1 and XBB.1.5) seem to escape immunity conferred by vaccination and previous infection.2Uraki R Ito M Furusawa Y et al.Humoral immune evasion of the omicron subvariants BQ.1.1 and XBB.Lancet Infect Dis. 2023; 23: 30-32Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar The US Food and Drug Administration proposed booster doses of bivalent mRNA vaccine specifically for immunocompromised patients in an effort to enhance protection for this vulnerable population. Data in small sets of immunocompetent persons demonstrate higher neutralisation against these variants after receiving a bivalent vaccine as well as protection against symptomatic infection.3Zou J Kurhade C Patel S et al.Neutralization of BA.4-BA.5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 with bivalent vaccine.N Engl J Med. 2023; 388: 854-857Crossref PubMed Scopus (21) Google Scholar, 4Link-Gelles R Ciesla AA Roper LE et al.Early estimates of bivalent mRNA booster dose vaccine effectiveness in preventing symptomatic SARS-CoV-2 infection attributable to omicron BA.5- and XBB/XBB.1.5-related sublineages among immunocompetent adults—increasing community access to testing program, United States, December 2022–January 2023.Morb Mortal Wkly Rep. 2023; 72: 119-124PubMed Google Scholar However, there is little data regarding humoral and cellular immune responses to new bivalent vaccine formulations in immunocompromised people specifically in relation to the currently circulating variants. We evaluated immunogenicity of the BA.4/5-bivalent vaccine to induce neutralising antibody and T-cell responses in immunosuppressed solid organ transplant recipients. Responses to BA.4/5, BQ.1.1, and XBB.1.5 were measured after bivalent vaccine and compared with cohorts either after monovalent vaccination or after SARS-CoV-2 infection. We used a pseudovirus variant-specific neutralisation assay to measure neutralising antibody in sera of 47 transplant recipients 4–6 weeks after receiving mRNA bivalent vaccine (divided into 25 patients with no history of COVID-19 and 22 patients with history of COVID-19). We compared the neutralising antibody response to those who received a fourth dose of monovalent vaccine (n=86), and to transplant cohorts after natural infection with either BA.1 (n=75) or BA.4/5 (n=50). Baseline characteristics across groups are shown in the appendix (pp 7–8). Results are shown in figure A. Although patients who received a bivalent booster had good neutralising titres against BA.4/5, the response to BQ.1.1 and XBB.1.5 was only marginally higher than the cohort that had previously received 4-doses of monovalent vaccine, and inferior to any cohort with previous infection (figure A; appendix p 13). For example, median titre against XBB.1.5 after bivalent vaccine in previously uninfected patients was 0 log10 ID50 (IQR 0–2·2) and ten (40·0%) of 25 patients had any detectable level of neutralisation. By contrast, previous Omicron infection with BA.5 resulted in significantly better neutralisation against both BQ.1.1 and XBB.1.5 (p<0·001 and p=0·003 respectively vs bivalent vaccine; figure A, appendix p 9). In the cohort that received bivalent vaccine, variant-specific SARS-CoV-2 CD4+ and CD8+ T-cell responses were measured using an intracellular cytokine staining flow cytometry assay (figure B) for BA.4/5 (n=35), BQ.1.1 (n=35) and XBB.1.5 (n=16). Both CD4+ and CD8+ T-cell responses were preserved across all three variants and were quite strong. For example, polyfunctional XBB.1.5-specific CD4+ T-cells were detected at a median frequency of 392 per 106 cells (IQR 97–1072) and were similar to that seen for BA.4/5 and BQ.1.1 after bivalent vaccine. The CD8+ T-cell response rate was lower than the CD4+ T-cell response but still preserved across variants. Previous infection with COVID-19 did not influence T-cells responses in this cohort (appendix p 7). Additionally, in a subset comparison of BA.4/5 and BQ.1.1 T-cell response before and after bivalent vaccine (n=9), no significant improvement was observed (appendix p 9). Similar results were observed comparing BA.4/5 T-cell responses after 4-dose monovalent and after bivalent vaccine (appendix p 14). Overall, our study suggests that, while bivalent vaccination increases BA.4/5-directed neutralising antibody in immunocompromised people, it only modestly impacts BQ.1.1 and XBB.1.5 neutralization. By contrast, substantial cross-protective neutralising antibody is observed following previous Omicron infection. T-cell responses are more readily detectable and conserved across BA.4/5, BQ.1.1, and XBB.1.5 variants, thereby possibly providing some cross-variant protection. However, no additional boosting of T-cell response was evident following bivalent vaccine. Our results suggest that, although vaccination is important, additional strategies such as the ongoing development of prophylactic monoclonal antibodies and use of early COVID-19 therapies are crucial for immunocompromised patients. DK has received clinical trials grants from GSK and Takeda and consulting fees from GSK, Takeda, Roche, Allovir, Merck, and Exevir. AH has received clinical trials grants from Merck and consulting fees from Merck and Takeda. ACG has received research funds from a research contract with Providence Therapeutics Holdings for other projects. The other authors declare no competing interests. Download .pdf (.9 MB) Help with pdf files Supplementary appendix