Immune suppression poses a challenge to vaccine immunogenicity. We show that serum antibody neutralization against SARS-CoV-2 Omicron descendants was largely absent post-doses 1 and 2 in individuals with vasculitis treated with rituximab. Detectable and increasing neutralizing titers were observed post-doses 3 and 4, except for XBB. Rituximab in vasculitis exacerbates neutralization deficits over standard immunosuppressive therapy, although impairment resolves over time since dosing. We observed discordance between detectable IgG binding and neutralizing activity specifically in the context of rituximab use, with high proportions of individuals showing reasonable IgG titer but no neutralization. ADCC response was more frequently detectable compared to neutralization in the context of rituximab, indicating that a notable proportion of binding antibodies are non-neutralizing. Therefore, use of rituximab is associated with severe impairment in neutralization against Omicron descendants despite repeated vaccinations, with better preservation of non-neutralizing antibody activity.

Neurocognitive impairment is an important cause of HIV-associated morbidity. The advent of antiretroviral therapy (ART) has shifted the spectrum of HIV-associated cognitive impairment from HIV-associated dementia to milder forms of cognitive impairment. Independent replication of HIV within the central nervous system in those on effective ART with peripheral suppression is a recognised phenomenon known as cerebrospinal fluid (CSF) HIV RNA escape. CSF HIV RNA escape is independently associated with neurocognitive impairment but has also been detected in asymptomatic persons with HIV. The current consensus for management of CSF HIV RNA escape is based on expert opinion rather than empirical evidence. The current evidence suggests having a low threshold to investigate for CSF HIV RNA escape and optimising ART based on resistance profiles. The use of central nervous system (CNS) penetration effectiveness scores is no longer recommended. The evidence for statins, SSRIs, minocycline, lithium and valproate is limited to small-scale studies. There are potential new developments in the form of nanoparticles, Janus Kinase inhibitors and latency reversal agents.

Age is a major risk factor for hospitalization and death after SARS-CoV-2 infection, even in vaccinees. Suboptimal responses to a primary vaccination course have been reported in the elderly, but there is little information regarding the impact of age on responses to booster third doses. Here we show that individuals 70 or older who received a primary two dose schedule with AZD1222 and booster third dose with mRNA vaccine achieved significantly lower neutralizing antibody responses against SARS-CoV-2 spike pseudotyped virus compared to those younger than 70. One month after the booster neither the concentration of serum binding anti spike IgG antibody, nor the frequency of spike-specific B cells showed differences by age grouping. However, the impaired neutralization potency and breadth post-third dose in the elderly was associated with enrichment of circulating “atypical” spike-specific B cells expressing CD11c and FCRL5. Single cell RNA sequencing confirmed an expansion of TBX21-, ITGAX -expressing B cells in the elderly that enriched for B cell activation/receptor signalling pathway genes. Importantly we also observed impaired T cell responses to SARS-CoV-2 spike peptides in the elderly post-booster, both in terms of IFNgamma and IL2 secretion, as well as a decrease in T cell receptor signalling pathway genes. This expansion of atypical B cells and impaired T cell responses may contribute to the generation of less affinity-matured antibodies, with lower neutralizing capacity post-third dose in the elderly. Altogether, our data reveal the extent and potential mechanistic underpinning of the impaired vaccine responses present in the elderly after a booster dose, contributing to their increased susceptibility to COVID-19 infection.

HIV associated neurocognitive disorder (HAND) remains an important HIV-associated comorbidity despite antiretrovirals (ARVs). Cerebrospinal fluid (CSF) escape/discordance is now recognised in the context of individuals with a reconstituted immune system with an estimated prevalence of 10%. However, the contribution of CSF escape/discordance to HAND remains uncertain. Furthermore, a latent reservoir of HIV in the brain has implications for lasting cure strategies. Little is known about the prevalence of CSF escape/discordance amongst people living with HIV (PLWH) in sub-Saharan Africa (SSA).We conducted a longitudinal cohort study of PLWH who were 18 years or older on ARVs for at least 1 year who reported neurocognitive complaints. We obtained paired CSF and blood at baseline, 6, 12 and 24 months. Viral load (VL) testing was done with the Abbott m2000 RealTime System. HIV genotyping was done by Sanger sequencing and next generation sequencing (NGS) by Illumina MiSeq. Resistance calling was done using Stanford HIV drug resistance database. Random drug levels were done on plasma and CSF using mass spectrometry.We present the results at baseline. Seven hundred and eight adult PLHIV attending a HIV treatment centre were screened using the Simioni symptom questionnaire and in addition asked “do you have a chronic, persistent headache?” Fifty-nine PLHIV answered yes to at least one of the screening questions and were considered for enrolment. Thirty consented to participate. The median age was 37.6 (IQR 33.2 to 48.3) years. The majority were women (98.0%, 28/30). Headache was the most common symptom (93.3%), then memory impairment (56.4%), attention deficit (48.3%) and impairment in executive functioning (46.7%). All participants had Karnofsky performance scale > 70% and were able to perform their activities of daily living independently. Symptoms of depression were common, with 82.8% scoring a CESD-R-10 >10. The median duration of ART was 9.9 (IQR 5.7 to 11.9) years. 72.4% (n=21/29) were on tenofovir/emtricitabine/efavirenz. The rest were on second line ARVs (ritonavir boosted lopinavir plus zidovudine/lamivudine or tenofovir/emtricitabine). The median nadir CD4 count was 193 (IQR 98 to 301) cells/mm3 and the current median CD4 count was 547 (IQR 384 to 856) cells/mm3. At baseline 86.2% had an undetectable plasma HIV viral load (<40 copies/ml) (25/29). Eighteen participants had paired CSF and blood successfully sampled. Of these 4 had detectable virus in the blood with VL ranging from 82 to 38,992 copies/ml. Two participants had CSF escape/discordance (9.0% (2/22) and 2 others had detectable VL in CSF but lower than the VL in blood. We found an association between detectable CSF VL and viraemia (p 0.001) and boosted protease inhibitor (PI) based ART (p 0.02). All participants who had undetectable VL in blood and CSF had detectable blood and CSF drugs levels corresponding to their prescribed ARVS. Two participants with detectable VL in the CSF had drug levels measured, which was below the limit of detection of the drug assays in both blood and CSF. Both participants were on second line boosted PI based ARVs. Viral sequencing revealed NNRTI resistance mutation G190A detected in both blood and CSF in the participant with CSF discordance and NRTI M184V, NNRTI K103N and P225H in the blood but not CSF of the second participant. No minority variants were identified below 20% by NGS.Virological failure appears to be driven by poor treatment adherence. The results suggest that the prevalence of CSF escape/discordance in HIV positive neurosymptomatic persons is consistent with previously published prevalence from resource rich settings however this needs to be explored in the larger study. Symptoms of depression were common and may bias self-reported neurocognitive impairment and needs to be explored further. This ongoing longitudinal study will also investigate the evolution of drug resistant variants in CSF and the relationship with plasma viral quasispecies.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementWe are thankful to the volunteers who participated in the study. R.K.G is supported by Wellcome Senior Fellowship in Clinical Science (WT108082AIA). D.A.C supported by Wellcome PhD Programme for Clinicians (206440/Z/17/Z). The study was supported by The Rosetrees Trust.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Approval was granted by UKZN Biomedical Research Ethics Committee BE604/17 and the University College Hospital Research Ethics Committee 14865/001.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors

Background: National lockdowns have led to significant interruption to children’s education globally. In the Autumn term in 2020, school absence in England and Wales was almost five times higher than the same period in 2019. Transmission of SARS-CoV-2 in schools and ongoing interruption to education remains a concern. However, evaluation of rapid point of care (POC) polymerase chain reaction (PCR) testing in British schools has not been undertaken. Methods: This is a survey of secondary schools in England that implemented PCR-based rapid POC testing. The study aims to measure the prevalence of SARS-CoV-2 infection in schools, to assess the impact of this testing on school attendance and closures, and to describe schools experiences with testing. All schools utilised the SAMBA II SARS-CoV-2 testing platform. Results: 12 fee-paying secondary schools in England were included. Between September 1st 2020 and December 16th 2020, 697 on site rapid POC PCR tests were performed and 6.7% of these were positive for SARS-CoV-2 infection. There were five outbreaks in three schools during this time which were contained. Seven groups of close contacts within the school known as bubbles had to quarantine but there were no school closures. 84% of those tested were absent from school for less than one day whilst awaiting their test result. This potentially saved between 1047 and 1570 days off school in those testing negative compared to the NHS PCR laboratory test. Schools reported a positive impact of having a rapid testing platform as it allowed them to function as fully as possible during this pandemic. Conclusions: Rapid POC PCR testing platforms should be widely available and utilised in school settings. Reliable positive tests will prevent outbreaks and uncontrolled spread of infection within school settings. Reliable negative test results will reassure students, parents and staff and prevent disruption to education.

OBJECTIVES:Population-based universal test and treat (UTT) trials have shown an impact on population-level virological suppression. We followed the ANRS 12249 TasP trial population for 6 years to determine whether the intervention had longer-term survival benefits. METHODS:The TasP trial was a cluster-randomized trial in South Africa from 2012 to 2016. All households were offered 6-monthly home-based HIV testing. Immediate antiretroviral therapy (ART) was offered through trial clinics to all people living with HIV (PLHIV) in intervention clusters and according to national guidelines in control clusters. After the trial, individuals attending the trial clinics were transferred to the public ART programme. Deaths were ascertained through annual demographic surveillance. Random-effects Poisson regression was used to estimate the effect of trial arm on mortality among (i) all PLHIV; (ii) PLHIV aware of their status and not on ART at trial entry; and (iii) PHLIV who started ART during the trial. RESULTS:Mortality rates among PLHIV were 9.3/1000 and 10.4/1000 person-years in the control and intervention arms, respectively. There was no evidence that the intervention decreased mortality among all PLHIV [adjusted rate ratio (aRR) = 1.10, 95% confidence interval (CI) = 0.85-1.43, p = 0.46] or among PLHIV who were aware of their status but not on ART. Among individuals who initiated ART, the intervention decreased mortality during the trial (aRR = 0.49, 95% CI = 0.28-0.85, p = 0.01), but not after the trial ended. CONCLUSIONS:The 'treat all' strategy reduced mortality among individuals who started ART but not among all PLHIV. To achieve maximum benefit of immediate ART, barriers to ART uptake and retention in care need to be addressed.

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals. Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

Background: National lockdowns have led to significant interruption to children’s education globally. In the Autumn term in 2020, school absence in England and Wales was almost five times higher than the same period in 2019. Transmission of SARS-CoV-2 in schools and ongoing interruption to education remains a concern. However, evaluation of rapid point of care (POC) polymerase chain reaction (PCR) testing in British schools has not been undertaken. Methods: This is a survey of secondary schools in England that implemented PCR-based rapid POC testing. The study aims to measure the prevalence of SARS-CoV-2 infection in schools, to assess the impact of this testing on school attendance and closures, and to describe schools experiences with testing. All schools utilised the SAMBA II SARS-CoV-2 testing platform. Results: 12 fee-paying secondary schools in England were included. Between September 1st 2020 and December 16th 2020, 697 on site rapid POC PCR tests were performed and 6.7% of these were positive for SARS-CoV-2 infection. There were five outbreaks in three schools during this time which were contained. Seven groups of close contacts within the school known as bubbles had to quarantine but there were no school closures. 84% of those tested were absent from school for less than one day whilst awaiting their test result. This potentially saved between 1047 and 1570 days off school in those testing negative compared to the NHS PCR laboratory test. Schools reported a positive impact of having a rapid testing platform as it allowed them to function as fully as possible during this pandemic. Conclusions: Rapid POC PCR testing platforms should be widely Open Peer Review Reviewer Status AWAITING PEER REVIEW Any reports and responses or comments on the article can be found at the end of the article. Page 1 of 7 Wellcome Open Research 2022, 7:8 Last updated: 11 JAN 2022

Background: National lockdowns have led to significant interruption to children’s education globally. In the Autumn term in 2020, school absence in England and Wales was almost five times higher than the same period in 2019. Transmission of SARS-CoV-2 in schools and ongoing interruption to education remains a concern. However, evaluation of rapid point of care (POC) polymerase chain reaction (PCR) testing in British schools has not been undertaken. Methods: This is a survey of secondary schools in England that implemented PCR-based rapid POC testing. The study aims to measure the prevalence of SARS-CoV-2 infection in schools, to assess the impact of this testing on school attendance and closures, and to describe schools experiences with testing. All schools utilised the SAMBA II SARS-CoV-2 testing platform. Results: 12 fee-paying secondary schools in England were included. Between September 1st 2020 and December 16th 2020, 697 on site rapid POC PCR tests were performed and 6.7% of these were positive for SARS-CoV-2 infection. There were five outbreaks in three schools during this time which were contained. Seven groups of close contacts within the school known as bubbles had to quarantine but there were no school closures. 84% of those tested were absent from school for less than one day whilst awaiting their test result. This potentially saved between 1047 and 1570 days off school in those testing negative compared to the NHS PCR laboratory test. Schools reported a positive impact of having a rapid testing platform as it allowed them to function as fully as possible during this pandemic. Conclusions: Rapid POC PCR testing platforms should be widely available and utilised in school settings. Reliable positive tests will prevent outbreaks and uncontrolled spread of infection within school settings. Reliable negative test results will reassure students, parents and staff and prevent disruption to education.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) transmission is uncontrolled in many parts of the world, compounded in some areas by higher transmission potential of the B1.1.7 variant now seen in 50 countries. It is unclear whether responses to SARS-CoV-2 vaccines based on the prototypic strain will be impacted by mutations found in B.1.1.7. Here we assessed immune responses following vaccination with mRNA-based vaccine BNT162b2. We measured neutralising antibody responses following a single immunization using pseudoviruses expressing the wild-type Spike protein or the 8 amino acid mutations found in the B.1.1.7 spike protein. The vaccine sera exhibited a broad range of neutralising titres against the wild-type pseudoviruses that were modestly reduced against B.1.1.7 variant. This reduction was also evident in sera from some convalescent patients. Decreased B.1.1.7 neutralisation was also observed with monoclonal antibodies targeting the N-terminal domain (9 out of 10), the Receptor Binding Motif (RBM) (5 out of 31), but not in neutralising mAbs binding outside the RBM. Introduction of the E484K mutation in a B.1.1.7 background to reflect newly emerging viruses in the UK led to a more substantial loss of neutralising activity by vaccine-elicited antibodies and mAbs (19 out of 31) over that conferred by the B.1.1.7 mutations alone. E484K emergence on a B.1.1.7 background represents a threat to the vaccine BNT162b.

The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha) 1 . In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era.

We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike Delta H69N70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although Delta H69N70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. Delta H69N70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where Delta H69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1 1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on Delta H69/V70. Therefore, as Delta H69N70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted.

The Omicron variant emerged in southern Africa in late 2021 and is characterised by multiple spike mutations across all spike domains. Here we show that the Omicron spike confers very significant evasion of vaccine elicited neutralising antibodies that is more pronounced for ChAdOx-1 adenovirus vectored vaccine versus BNT162b2 mRNA vaccine. Indeed neutralisation of Omicron was not detectable for the majority of individuals who had received two doses of ChAdOx-1. Third dose mRNA vaccination rescues neutralisation in the short term. Despite three mutations predicted to favour spike S1/S2 cleavage, observed cleavage efficiency is lower than for wild type Wuhan-1 D614G and Delta. We demonstrate significantly lower infectivity of lung organoids and Calu-3 lung cells expressing endogenous levels of ACE2 and TMPRSS2 but similar infection as compared to Delta when using H1299 lung epithelial cells. Importantly, fusogenicity of the Omicron spike is impaired, leading to marked reduction in syncitia formation. These observations indicate that Omicron has gained immune evasion properties whilst possibly modulating properties associated with replication and pathogenicity.

SARS-CoV-2 amino acid replacements in the receptor binding domain (RBD) occur relatively frequently and some have a consequence for immune recognition. Here we report recurrent emergence and significant onward transmission of a six-nucleotide out of frame deletion in the S gene, which results in loss of two amino acids: H69 and V70. We report that in human infections ΔH69/V70 often co-occurs with the receptor binding motif amino acid replacements N501Y, N439K and Y453F, and in the latter two cases has followed the RBD mutation. One of the ΔH69/V70+ N501Y lineages, now known as B.1.1.7, has undergone rapid expansion and includes eight S gene mutations: RBD (N501Y and A570D), S1 (ΔH69/V70 and Δ144) and S2 (P681H, T716I, S982A and D1118H). In vitro , we show that ΔH69/V70 does not reduce serum neutralisation across multiple convalescent sera. However, ΔH69/V70 increases infectivity and is associated with increased incorporation of cleaved spike into virions. ΔH69/V70 is able to compensate for small infectivity defects induced by RBD mutations N501Y, N439K and Y453F. In addition, replacement of H69 and V70 residues in the B.1.1.7 spike reduces its infectivity and spike mediated cell-cell fusion. Based on our data ΔH69/V70 likely acts as a permissive mutation that allows acquisition of otherwise deleterious immune escape mutations. Enhanced surveillance for the ΔH69/V70 deletion with and without RBD mutations should be considered as a global priority not only as a marker for the B.1.1.7 variant, but potentially also for other emerging variants of concern. Vaccines designed to target the deleted spike protein could mitigate against its emergence as increased selective forces from immunity and vaccines increase globally. Highlights ΔH69/V70 is present in at least 28 SARS-CoV-2 lineages ΔH69/V70 does not confer escape from convalescent sera ΔH69/V70 increases spike infectivity and compensates for RBD mutations ΔH69/V70 is associated with greater spike cleavage B.1.1.7 requires ΔH69/V70 for optimal spike cleavage and infectivity

The SARS-CoV-2 B.1.617.2 (Delta) variant was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha). In vitro , B.1.617.2 is 6-fold less sensitive to serum neutralising antibodies from recovered individuals, and 8-fold less sensitive to vaccine-elicited antibodies as compared to wild type Wuhan-1 bearing D614G. Serum neutralising titres against B.1.617.2 were lower in ChAdOx-1 versus BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies against the receptor binding domain (RBD) and N-terminal domain (NTD), in particular to the clinically approved bamlavinimab and imdevimab monoclonal antibodies. B.1.617.2 demonstrated higher replication efficiency in both airway organoid and human airway epithelial systems as compared to B.1.1.7, associated with B.1.617.2 spike being in a predominantly cleaved state compared to B.1.1.7. Additionally we observed that B.1.617.2 had higher replication and spike mediated entry as compared to B.1.617.1, potentially explaining B.1.617.2 dominance. In an analysis of over 130 SARS-CoV-2 infected healthcare workers across three centres in India during a period of mixed lineage circulation, we observed substantially reduced ChAdOx-1 vaccine efficacy against B.1.617.2 relative to non-B.1.617.2. Compromised vaccine efficacy against the highly fit and immune evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era.

Two dose mRNA vaccination provides excellent protection against SARS-CoV-2. However, there are few data on vaccine efficacy in elderly individuals above the age of 801. Additionally, new variants of concern (VOC) with reduced sensitivity to neutralising antibodies have raised fears for vulnerable groups. Here we assessed humoral and cellular immune responses following vaccination with mRNA vaccine BNT162b22 in elderly participants prospectively recruited from the community and younger health care workers. Median age was 72 years and 51% were females amongst 140 participants. Neutralising antibody responses after the first vaccine dose diminished with increasing age, with a marked drop in participants over 80 years old. Sera from participants below and above 80 showed significantly lower neutralisation potency against B.1.1.7, B.1.351 and P.1. variants of concern as compared to wild type. Those over 80 were more likely to lack any neutralisation against VOC compared to younger participants following first dose. The adjusted odds ratio for inadequate neutralisation activity against the B.1.1.7, P.1 and B.1.351 variant in the older versus younger age group was 4.3 (95% CI 2.0-9.3, p<0.001), 6.7 (95% CI 1.7-26.3, p=0.008) and 1.7 (95% CI 0.5-5.7, p=0.41). Binding IgG and IgA antibodies were lower in the elderly, as was the frequency of SARS-CoV-2 Spike specific B-memory cells. We observed a trend towards lower somatic hypermutation in participants with suboptimal neutralisation, and elderly participants demonstrated clear reduction in class switched somatic hypermutation, driven by the IgA1/2 isotype. SARS-CoV-2 Spike specific T-cell IFNγ and IL-2 responses fell with increasing age, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high risk population that warrant specific measures in order to mitigate against vaccine failure, particularly where variants of concern are circulating.