Reduced risk for Omicron SARS-CoV-2 infection observed in older adults with hybrid immunity

Abstract

Key Points

• Hybrid immunity in older adults may reduce the risk of symptomatic Omicron SARS-CoV-2 infection.

• Hybrid SARS-CoV-2 immunity highlights key groups among older adults that may benefit from booster vaccination.

• Representative data in older adults key for the SARS-CoV-2 booster vaccination strategy.

Introduction

Hybrid SARS-CoV-2 immunity, derived from a combination of natural infection and immunisation, may provide protection for longer durations against hospitalisation and severe disease, compared to either infection or immunisation alone [1]. This effect has been observed following infection with more recent variants (e.g. Omicron) and may inform future targeted booster immunisation strategies [1].

Older adults remain a target population for ongoing booster campaigns, with the World Health Organisation highlighting considerable variation in the completion of either primary or booster campaigns across different countries [2, 3]. Primary research data are considerably skewed to younger adults, however, making it difficult to practically extrapolate findings to high-risk groups and inform public health strategy in response to further emergent variants of concern [1, 4]. Older adults in the UK with SARS-CoV-2 infection have experienced the highest rates of hospitalisation with admission rates of 4.9/100 000 in those 65–84 and 17/100 000 in those >85 years old. Despite this, booster vaccination campaigns targeting the 2023–2024 winter period had limited uptake in some regions.

Autumn 2023 boosters, e.g. were only administered to 32% of >65 year olds in some areas of London [5]. We report here the incidence of a new SARS-CoV-2 infection, and correlate these against previously established laboratory immunological parameters, to explore the differential protective effect of hybrid versus vaccine-only immunity for Omicron variant SARS-CoV-2 infection in older adults living in a long-term care facility (LTCF) in London.

Methods

A prospective longitudinal observational study was conducted at the Royal Hospital Chelsea, a 290-bed LTCF in the Royal Borough of Chelsea and Kensington was studied between March 2020 and April 2022 (SARS-Cov-2 antibody response in oLder PEopLe; SCALPEL, Research Ethics Committee Reference no. 22/EE/0083).

The Royal Hospital Chelsea is a dedicated residential and care home for UK military veterans, with 68 residential care and nursing beds. One ward specialises in dementia care. Site lockdown was instigated on 19 March 2020, prior to the national lockdown with the relaxation of restrictions for visitors on 19 July 2021 [6]. Onsite primary care was intermittently bolstered with additional support from Royal Army Medical Corps personnel and secondary care advice (or clinical support where admission was required) from infectious diseases, medical microbiology and respiratory medicine at Chelsea and Westminster Hospital. Public health and infection prevention and control support was provided by the Army’s Senior Health Advisor team.

Investigators explained the study to small groups of potential participants, and a participant information sheet in large print was provided. Individual explanations were provided for those with mild visual/hearing impairments. Suitable time (>48 hrs) was then provided to consider the information and ask questions before residents were invited to participate in the study. If a resident opted to participate, individual consent forms were explained and signed. The consent process was repeated prior to any occasion on which a blood sample was taken. The inclusion criteria included any LTCF resident who received a Pfizer BioNTech vaccination course and was able to give written informed consent. Exclusion criteria included those unable to provide written informed consent (including, e.g. those with advanced dementia). The vaccination was delivered by Pfizer BioNTech (1st dose December 2020, 2nd dose April 2021 and 1st booster October 2021) [6].

SCALPEL’s primary objective to explore the effect of hybrid immunity in older adults on antibody response in the context of Pfizer BioNTech immunisation has previously been reported [6]. In the SCALPEL study, antibody responses were assessed by a series of assays, including SARS-CoV-2 anti-nucleocapsid and anti-receptor binding domain antibodies, SARS-CoV-2 pseudotype virus neutralisations and competitive enzyme-linked immunosorbent assays/inhibition assays [6]. SCALPEL’s secondary objective, reported here, was to assess the relationship between SARS-CoV-2 breakthrough infection and hybrid immunity in older adults. In addition to prior reported findings [6], this study examines the association between breakthrough infection and immunity across a further 6-month period, during which the UK experienced the emergence and dominance of the Omicron variant.

Assessing hybrid immunity status

Prior natural infection was established by a combination of a thorough antigen screening approach, supplemented by antibody testing. All participants underwent routine weekly asymptomatic SARS-CoV-2 screening during the duration of the study, instigated from March 2020 onwards. Screening was conducted via polymerase chain reaction of nasopharyngeal swabs using a variety of ce marked systems as previously described from Thermo Fisher Scientific, USA; Roche Holding AG, Basel, Switzerland; and AusDiagnostics, Sydney, Australia [6]. Additional testing was conducted for: (i) symptomatic patients as per UK guidance and (ii) increased screening (twice weekly) for asymptomatic individuals living in adjacent rooms to a known positive case. Symptomatic infection was defined as per UK Health Security Agency guidance [7].

Antigen testing was supplemented by periodic SARS-CoV-2 anti-nucleocapsid antibody testing (which can be detected in serum following a natural infection but is not developed in response to vaccine stimuli) using the Abbott anti-NP IgG chemiluminescent microparticle immunoassay (Abbott Laboratories, Lake Bluff, IL, USA) as per manufacturer instructions. Periodic serological testing was conducted in June 2020 (as the UK first wave of SARS-CoV-2 infection declined), prior to first dose of vaccine (December 2020), 4 weeks post-second dose of vaccine (April 2021), 4 weeks post-third dose of vaccine (October 2021) and 4 weeks post-fourth dose of vaccine (April 2022).

Assessment of breakthrough infection post-second dose vaccine

Participants were observed for breakthrough infections between the third dose of vaccine (October 2021) and the fourth dose of vaccine (April 2022). Phylogenetic Assignment of Named Global Outbreak Lineages (Pangolin) surveillance in the UK during the study period showed dominance of Omicron and its sub-lineages by the beginning of December 2021 through the end of the study period [8]. At the end of the study, those with signs of infection, either by PCR or first-time anti-NP seroconversion, were compared between those with and without evidence of hybrid infection prior to infection.

Statistical analysis

Participant demographics were analysed using descriptive statistics. The incidence of infection was compared between those with and without evidence of hybrid immunity by unadjusted odds ratios and chi-squared. Odds ratios for asymptomatic versus symptomatic infection were then compared between those with and without evidence of hybrid immunity using a likelihood ratio test. The significance thresholds were set at 0.05.

Results

280/319 (87.8%) potential participants (median age 82 yrs, IQR 76-88 yrs; 95.4% male), met the inclusion criteria, consented and were followed up. 168/280 (60%) had evidence of hybrid immunity prior to the Omicron variant wave. Four individuals were considered to be immunosuppressed at the time of infection due to high-dose steroids (one) or methotrexate (one) in the vaccine-only immunity group and due to current leukaemia and interstitial lung disease (one) and prior splenectomy (one) in the hybrid immunity group.

During the UK Omicron-dominant wave between December 2021 and April 2022, 21/168 (12.5%) participants with hybrid immunity developed infection, while 40/112 (35.7%) of those with vaccine-only derived immunity developed infection. Participants who had hybrid immunity prior to Omicron had substantially lower odds of later acquiring COVID-19 (unadjusted odds ratio 0.26, 95% CI 0.14–0.47, chi-squared P < .0001).

Compared to those with vaccine-only immunity, participants with hybrid immunity had an odds ratio of 0.40 (0.19–0.79) for asymptomatic infection and 0.15 (0.06–0.34) for symptomatic infection (Likelihood ratio test, P < .0001). Of patients with recognised causes for immunosuppression, all cases of infection were considered mild. Of participants with detected infection among those with hybrid immunity, 1/21 developed signs of severe infection requiring admission to secondary care and oxygen support. There was a background history of prostate cancer and type 2 diabetes mellitus. This participant died within 30 days of diagnosis, with the cause of death thought to be community-acquired bacterial pneumonia complicated by Klebsiella pneumonia bacteraemia. Of participants with vaccine-only derived immunity, all cases of infection were considered to be mild, and none required admitting to secondary care.

Discussion

Greater representation of older adults among primary research on the protective effects of hybrid immunity has been highlighted as a priority if data are to practically inform booster vaccination strategies [1, 4, 6]. In this study, we have observed encouraging results with reduced risk seen for both asymptomatic and symptomatic SARS-CoV-2 Omicron variant infection in older adults with hybrid immunity, compared to those who had vaccine-only immunoprotection.

Our data highlight the potential protective benefit of hybrid immunity in this group and, if replicated across larger cohorts, the possibility of targeted vaccination strategies that could see those with hybrid immunity requiring less frequent booster immunisation. This may be particularly important in the context of a preliminary COVID-19 vaccine safety signal raised by the US Food and Drug Administration and the Centre for Communicable Diseases for those over 65 years old [9]. While current assessment suggests no changes are recommended for vaccination practices, further data on the protective effect of hybrid immunity could help optimise the risk–benefit analysis of continued booster vaccinations in this group. A considerable range in ongoing uptake of booster vaccinations, with the trend for lower rates in large city populations compared with more rural areas, (where the risk of infection is also likely to be higher), further raises the value of understanding risk factors for symptomatic infection among different at-risk populations for severe disease.

Our data are limited by its small cohort size and predominantly male distribution. Where prior studies have suggested reduced vaccine immunogenicity and a more severe infection profile among males, it is possible that our findings may be influenced by survivor bias [10]. Given the predominant male distribution of our data and high vaccine uptake, caution should be applied in generalisation of our findings to non-veteran LTCF populations that are likely to see a more even male-to-female ratio and may differ in rates of vaccine uptake. Our data are is, however, strengthened by a robust screening process compared with similar studies by regular screening for hybrid immunity by both asymptomatic and symptomatic SARS-CoV-2 infection using a combination of antigen testing and serology [6]. While our data observe infection in the context of Omicron, data on risks associated with the emerging BA.2.86 variant have not shown any signals of concern for a change in phenotype [11].

Future studies must seek to include older adults as a key group and, where reported, provide detailed age-related data rather than a simple cut-off of >65 if such observations are to provide any practical support to wider public health vaccination strategies [1, 4, 5].

Acknowledgements:

The authors thank the Royal Hospital Chelsea, the Royal Hospital Chelsea Commissioners, members of the Royal Hospital Chelsea Research Oversight Committee, and in particular the Royal Hospital Chelsea In-Pensioners for their support. The authors also acknowledge the support of the Royal Hospital Chelsea Governor, General Sir Adrian Bradshaw KCB OBE. J.H. acknowledges support in the form of a research fellowship from CW+ and the Westminster Medical School Research Trust. L.S.P.M. acknowledges support from the National Institute of Health Research (NIHR) Imperial Biomedical Research Centre (BRC) and the National Institute for Health Research Health Protection Research Unit (HPRU) in Healthcare Associated Infection and Antimicrobial Resistance at Imperial College London in partnership with Public Health England. The authors thank the Royal Hospital Chelsea Research Oversight Committee for their support in drafting the initial Integrated Research Application System submission. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, the UK Ministry of Defence or the UK Department of Health.

Declaration of Conflicts of Interest:

L.S.P.M. has consulted for or received speaker fees from bioMerieux (2013–2023), Eumedica (2016–2022), Pfizer (2018–2023), Umovis Lab (2020–2021), Kent Pharma (2021), Pulmocide (2020–2021), Sumiovant (2021–2023), Shionogi (2021–2023), and Qiagen (2023) and received research grants from the National Institute for Health Research (2013–2023), CW+ Charity (2018–2023), North West London Pathology (2022–2023), and LifeArc (2020–2022). RJ has received funding to attend conferences or educational meetings, honoraria and/or funding for research from Gilead Sciences, Bristol-Myers Squibb, Janssen-Cilag, GlaxoSmithKline/ ViiV healthcare and Abbvie. S.J.C.P. has received a research grant from the Scientific Exploration Society. All other authors have no conflicts of interest to declare.

Declaration of Sources of Funding:

Funding was provided by the Chelsea INfectious DiseasEs Research (CINDER) fund.

Data availability:

A copy of data is available from the corresponding author (S.J.C.P.; [email protected]) on reasonable request, as long as this meets local ethical and research governance.

A copy of custom code (R) is available from the statistician ([email protected]) on reasonable request, as long as this meets local ethical and research governance.

References