Robust generation of neutralising antibodies against Omicron variants following bivalent mRNA booster vaccine in elderly people aged >80 years

Dear Editor, We were very interested to read the report of Whitaker and colleagues which assessed the efficacy of COVID-19 vaccines in clinical risk groups in the pre-Omicron era. This highlighted the fact that vaccine-induced protection, whilst overall retaining high efficacy, was reduced in this population with a >3-fold increased fatality rate following recent infection in immune suppressed patients. Elderly people aged >80 years are also an important clinical risk group and remain at markedly increased risk of mortality following SARS-CoV-2 infection. Furthremore the evolution of Omicron lineages has necessitated the development of bivalent vaccines that comprise mRNA encoding pre-Omicron and Omicron spike protein. Despite this, there has been no assessment of the immunogenicity of bivalent vaccines in this age group. SARS-CoV-2 continues to cause considerable morbidity and mortality within the most vulnerable populations including the elderly, patients with multimorbidity, and the immune suppressed. Patients over the age of 80 years are particularly vulnerable with a >8.1-fold increased risk of severe clinical outcomes despite vaccination.1Agrawal U. Bedston S. McCowan C. Oke J. Patterson L. Robertson C. et al.Severe COVID-19 outcomes after full vaccination of primary schedule and initial boosters: pooled analysis of national prospective cohort studies of 30 million individuals in England, Northern Ireland, Scotland, and Wales.Lancet. 2022; 400: 1305-1320Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Despite the remarkable success of COVID-19 vaccines, booster doses are required to maintain antibody levels and enhance antibody affinity against viral variants. Furthermore, since displacement of ancestral SARS-CoV-2 by Omicron variants, bivalent mRNA vaccines that encode for both ancestral and Omicron spike protein have been introduced in many national programmes.2Chalkias S. Harper C. Vrbicky K. Walsh S.R. Essink B. Brosz A. et al.A bivalent Omicron-containing booster vaccine against Covid-19.N Engl J Med. 2022; 387: 1279-1291Crossref PubMed Scopus (242) Google Scholar Despite this, there is currently no information on the immunogenicity of bivalent vaccines in very elderly people above the age of 80 years. This information is needed in order to understand the efficacy of bivalent vaccine regimens and to support population confidence in their adoption, the uptake of which remains suboptimal.3Alcendor D.J. Matthews-Juarez P. Smoot D. Edwards A. Hildreth J.E.K. Juarez P.D. Vaccine confidence and uptake of the Omicron bivalent booster in Tennessee: implications for vulnerable populations.Vaccines. 2023; 11: 906Crossref PubMed Scopus (2) Google Scholar We studied antibody and cellular immune responses to SARS-CoV-2 bivalent vaccination in a cohort of 103 people of median age 84 years (81–87) who are living independently. This cohort had been followed prospectively since their initial vaccination and the mRNA bivalent booster represented their 5th COVID-19 vaccine.4Parry H. Bruton R. Ayodele R. Sylla P. McIlroy G. Logan N. et al.Vaccine subtype and dose interval determine immunogenicity of primary series COVID-19 vaccines in older people.Cell Rep Med. 2022; 3100739Google Scholar 45% had serological evidence of prior SARS-CoV-2 infection. All donors received either the Moderna Spikevax bivalent Original/Omicron BA.1 vaccine or Pfizer Comirnaty Original/Omicron BA.1 vaccine. Blood samples were taken immediately prior to, and then at 24 days following, vaccination. Comparable sampling had been obtained on the same donors 5–6 months previously for the 4th COVID-19 mRNA vaccine, comprising solely ancestral SARS-CoV-2 spike (n = 94). Initial studies determined the antibody titre against ancestral and Omicron spike protein following 5th (bivalent) vaccination. Antibody titre increased 2.2 fold against ancestral spike but 3.8 fold against omicron and peak values were 28% and 62% greater respectively than following 4th dose peak response (A). Of note, donors had received one of three primary series vaccination schedules, comprising standard or extended interval mRNA vaccine or ChAdOx1. Although these regimens had elicited differential immune responses in earlier assessments, no residual influence of primary series vaccine choice was seen at this stage. T cell immune recognition of spike protein was determined using QuantiFERON IFN-γ cytokine release assay. An 4.3-fold increment in response was seen following bivalent vaccine with peak responses 2.3-fold higher than following fourth vaccination (B). As the majority of spike-specific T-cell responses are shared between ancestral and omicron proteins these findings augur well for effective cellular immunity in this elderly group.5Tarke A. Coelho C.H. Zhang Z. Dan J.M. Yu E.D. Methot N. et al.SARS-CoV-2 vaccination induces immunological T cell memory able to cross-recognize variants from Alpha to Omicron.Cell. 2022; 185: 847-859Abstract Full Text Full Text PDF PubMed Scopus (448) Google Scholar We next determined antibody-mediated neutralisation of viral variants using pseudotyped viral infection assays. Neutralisation of ancestral virus was strong following bivalent vaccination but not increased above 4th vaccine peak response. In contrast, neutralising antibody titres increased 5.8 fold against Omicron BA.1 following bivalent delivery, indicating relative enhancement of neutralisation (C) and comparable to results seen in younger donors.6Wang W. Goguet E. Paz S. Vassell R. Pollett S. Mitre E. et al.Bivalent coronavirus disease 2019 vaccine antibody responses to Omicron variants suggest that responses to divergent variants would be improved with matched vaccine antigens.J Infect Dis. 2023; 228: 439-443Crossref PubMed Scopus (2) Google Scholar Neutralisation of omicron subvariants was also undertaken as these now dominate the infection landscape. As prior SARS-CoV-2 infection enhances neutralisation, these values were determined in relation to infection status in order to ensure that antibody titres were adequate in infection-naïve people. This is particularly important as many vulnerable older people limited social contact during the COVID-19 pandemic. Neutralisation of ancestral and BA.1 virus was strong although peak responses remained lower in infection-naïve donors with a similar profile seen against BA 2.75 and BQ1.1 variants. However, although neutralising antibodies against the XBB subvariant were virtually undetectable prior to bivalent vaccine delivery, these increased substantially following vaccination and this response was independent of infection status (D). These data show that bivalent vaccination markedly enhances serum neutralising activity against currently dominant omicron subvariants in elderly people, irrespective of infection status. It is now established that elderly people, who remain at greatest risk of severe clinical outcomes, require regular COVID-19 booster vaccination to maintain relative clinical protection. However, this demographic group has largely been excluded from registration clinical trials, most notably in relation to bivalent vaccines. Here we show that strong antibody and cellular responses against Omicron spike are generated in very elderly people following BA.1 bivalent vaccination. Indeed, antibody levels are comparable to those seen within younger donors. Furthermore, antibody neutralisation, an accepted immune correlate of vaccine protection, is strongly enhanced following bivalent vaccination. These findings support policy programmes of bivalent vaccine delivery to older people and should encourage efforts to optimise uptake within this very vulnerable group. A.Spike-specific antibody titre against Ancestral B.1 and Omicron BA.1 before and after monovalent (n = 84) or bivalent (n = 103) vaccine. (p < 0.0001 Kruskal-Wallis with p = 0.04 for Bivalent response to BA.1 by multiple comparison).B.Spike-specific cellular response by QuantiFERON IFN-g release following monovalent (n = 42) or bivalent vaccine (n = 25; p = 0.007 Mann Whitney).C.Neutralization titre against ancestral B.1 or Omicron BA.1 following monovalent or bivalent vaccine. Paired values from individual donors are shown (B .1 n = 24; BA .1 n = 16). (p = 0.0399; Kruskal Wallis. Multiple comparisons BA.1 comparison p = 0.0008). Geometric mean and 95% CI shown).D.Neutralising antibody titre against SARS-CoV-2 variants following bivalent vaccine according to prior SARS-CoV-2 infection status (n = 46; Kruskal-Wallis p < 0.0001; (multiple comparisons showing: BA.1 pre and post with no prior infection (p = 0.0003) and with prior infection (p = 0.01); XBB with no prior infection (p = <0.0001) Geometric mean shown). P.M. declares renumeration for educational meeting and advisory board work at Astra Zeneca and for educational meetings with Moderna. H.P. declares renumeration for educational meeting and advisory board work at Astra Zeneca. Other authors declare no competing interests. We thank Dr. Rory Meade, Dr. Philip Saunders, Dr. Rosie Laugharne, Dr. Tom Groves, Dr. Parjit Dhillon, Dr. Eleanor Brodie, and the patients and staff at Harborne Medical Practice, Lordswod Medical Group, Ridgacre House Surgery, Northumberland House Surgery, New Road Surgery, Lapal Medical Practice, and Wychbury Medical Group. We also thank Millie Manning, Danielle Sutherland for their help in recruitment. We are grateful for support from Rajinder Jeet, Shahada Rahman Joli, Anindita Roy and Ayaz Karim with phlebotomy services. This work was supported by the UK Coronavirus Immunology Consortium (UK-CIC) MR/V028448/1 awarded to PM, in addition to funding from DHSC/UKRI and the National Core Studies Immunity programme MC_PC_20031 and MC_PC_20060 awarded to PM. Additional support to B.W. from MRC (MC_UU_00034/6P).