Individuals with potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not necessarily develop PCR or antibody positivity, suggesting that some individuals may clear subclinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1–3. Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. 4–11), would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T cells, including those against the early transcribed replication–transcription complex (RTC)12,13, in intensively monitored healthcare workers (HCWs) who tested repeatedly negative according to PCR, antibody binding and neutralization assays (seronegative HCWs (SN-HCWs)). SN-HCWs had stronger, more multispecific memory T cells compared with a cohort of unexposed individuals from before the pandemic (prepandemic cohort), and these cells were more frequently directed against the RTC than the structural-protein-dominated responses observed after detectable infection (matched concurrent cohort). SN-HCWs with the strongest RTC-specific T cells had an increase in IFI27, a robust early innate signature of SARS-CoV-2 (ref. 14), suggesting abortive infection. RNA polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA polymerase was preferentially targeted (among the regions tested) by T cells from prepandemic cohorts and SN-HCWs. RTC-epitope-specific T cells that cross-recognized HCoV variants were identified in SN-HCWs. Enriched pre-existing RNA-polymerase-specific T cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T cells as targets for vaccines against endemic and emerging Coronaviridae.

The immune response to SARS-CoV-2 is critical in controlling disease but there is concern that waning immunity may predispose to re-infection. We analysed the magnitude and phenotype of the SARS-CoV-2-specific T cell response in 100 donors at six months following infection. T-cell responses were present by ELISPOT and/or ICS analysis in all donors and characterised by predominant CD4+ T cell responses with strong IL-2 cytokine expression. Median T-cell responses were 50% higher in donors who had experienced a symptomatic infection indicating that the severity of primary infection establishes a ‘setpoint’ for cellular immunity. T-cell responses to spike and nucleoprotein/membrane proteins were correlated with peak antibody levels. Furthermore, higher levels of nucleoprotein-specific T cells were associated with preservation of NP-specific antibody level although no such correlation was observed in relation to spike-specific responses. In conclusion, our data are reassuring that functional SARS-CoV-2-specific T-cell responses are retained at six months following infection.

SARS-CoV-2 vaccine rollout has coincided with the spread of variants of concern. We investigated if single dose vaccination, with or without prior infection, confers cross protective immunity to variants. We analyzed T and B cell responses after first dose vaccination with the Pfizer/BioNTech mRNA vaccine BNT162b2 in healthcare workers (HCW) followed longitudinally, with or without prior Wuhan-Hu-1 SARS-CoV-2 infection. After one dose, individuals with prior infection showed enhanced T cell immunity, antibody secreting memory B cell response to spike and neutralizing antibodies effective against B.1.1.7 and B.1.351. By comparison, HCW receiving one vaccine dose without prior infection showed reduced immunity against variants. B.1.1.7 and B.1.351 spike mutations resulted in increased, abrogated or unchanged T cell responses depending on human leukocyte antigen (HLA) polymorphisms. Single dose vaccination with BNT162b2 in the context of prior infection with a heterologous variant substantially enhances neutralizing antibody responses against variants.

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The Omicron, or Pango lineage B.1.1.529, variant of SARS-CoV-2 carries multiple spike mutations with high transmissibility and partial neutralizing antibody (nAb) escape. Vaccinated individuals show protection from severe disease, often attributed to primed cellular immunity. We investigated T and B cell immunity against B.1.1.529 in triple mRNA vaccinated healthcare workers (HCW) with different SARS-CoV-2 infection histories. B and T cell immunity against previous variants of concern was enhanced in triple vaccinated individuals, but magnitude of T and B cell responses against B.1.1.529 spike protein was reduced. Immune imprinting by infection with the earlier B.1.1.7 (Alpha) variant resulted in less durable binding antibody against B.1.1.529. Previously infection-naïve HCW who became infected during the B.1.1.529 wave showed enhanced immunity against earlier variants, but reduced nAb potency and T cell responses against B.1.1.529 itself. Previous Wuhan Hu-1 infection abrogated T cell recognition and any enhanced cross-reactive neutralizing immunity on infection with B.1.1.529.

Understanding the nature of immunity following mild/asymptomatic infection with SARS-CoV-2 is crucial to controlling the pandemic. We analyzed T cell and neutralizing antibody responses in 136 healthcare workers (HCW) 16-18 weeks after United Kingdom lockdown, 76 of whom had mild/asymptomatic SARS-CoV-2 infection captured by serial sampling. Neutralizing antibodies (nAb) were present in 89% of previously infected HCW. T cell responses tended to be lower following asymptomatic infection than in those reporting case-definition symptoms of COVID-19, while nAb titers were maintained irrespective of symptoms. T cell and antibody responses were sometimes discordant. Eleven percent lacked nAb and had undetectable T cell responses to spike protein but had T cells reactive with other SARS-CoV-2 antigens. Our findings suggest that the majority of individuals with mild or asymptomatic SARS-CoV-2 infection carry nAb complemented by multispecific T cell responses at 16-18 weeks after mild or asymptomatic SARS-CoV-2 infection.

Human foreskin fibroblasts acutely infected with VZV were exposed to VZV antibody-posi.tive human serum and human mononuclear cells (MC) in a 6-hr 5 1~r release assay. Specific lysis could be detected by 60 min and was proportional to the effector cel1:target cell ratio. The reaction was temperature dependent, proceeding optimally at 37OC. Only VZV antibody-positive serum mediated the reaction, and uninfected targets were not lysed. MC alone had little or no lytic activity. Median antibody titers of 1000 were noted in the serum of normal adults without a history of zoster. The antibody was of the IgG class as indicated by its adsorption with S. aureus containing protein A, its presence in high titer in inunune serum globulin and zoster immune globulin, and its quantitative placental transfer. A requirement for effector cell IgG-Fc receptors was shown by blocking of ADCC by protein A and inhibition of effector cell activity by heat-aggregated gamma globulin. Lymphocytes were more effective as killer cells than were monocytes or polyorphonuclear leukocytes. ADCC was able to lyse cells earlier in the VZV infectious cycle than antibody-dependent complement-mediated lysis. These results are the first demonstration of ADCC against VZV-infected cells and suggest a mechanism whereby IgG antibody aids in prophylaxis of infection or reduces the severity of exogenous reinfection. I n the newborn, serum l e v e l s o f a l l 4 o f these proteins are normally reduced. Despite t h i s physiologic hypocomplementemia, umbilical cord blood shows a much higher r a t i o o f these components w i t h nearly 70% (n=200) o f neonates being greater than 1.3. These data suggest t h a t the a c t i v i t y o f B1H and C3bINA i n regulating the i n t e r a c t i o n o f C3 and f a c t o r B i s more potent i n the newborn. Measurement o f s p e c i f i c functional B1H a c t i v i t y revealed l i t t l e difference between the a d u l t and newborn i n the number o f B1H molecules required t o i n a c t i v a t e 1 e f f e c t i v e C3b molecule. By contrast, s p e c i f i c C3bINA functional assays demons t r a t e t h a t the newborn requires 50-75% fewer C3bINA molecules than the a d u l t i n order t o i n a c t i v a t e 1 e f f e c t i v e C3b molecule. Thus, the neonate appears t o have an a l t e r e d form o f C3bINA which i s 2-3 times more potent than i t s a d u l t counterpart. This a l t e r e d molecule could allow f o r less C3b deposition on an offending agent and, therefore, less e f f i c i e n t opsonization. The effect of inadequate dietar; iron uptake on cellular immune responses was studied in weanling female mice C57BLl6, which were fed either control (C), iron deficient (DEF) or pairfed (PF) C diets. The DEF mice showed a significant decrease in the delayed cutaneous hypersensitivity feaction to dinitroflurobenzene D FB) as measured by the inflammatory skin response (p<.001) and f2yI-dUR incorporation into sensitized ears (p<.001). When a sinfle dose of imferon was given to DEF mice prior to recall, the 251-~UR...

Background SARS-CoV-2 serology is used to identify prior infection at individual and at population level. Extended longitudinal studies with multi-timepoint sampling to evaluate dynamic changes in antibody levels are required to identify the time horizon in which these applications of serology are valid, and to explore the longevity of protective humoral immunity. Methods Healthcare workers were recruited to a prospective cohort study from the first SARS-CoV-2 epidemic peak in London, undergoing weekly symptom screen, viral PCR and blood sampling over 16–21 weeks. Serological analysis ( n =12,990) was performed using semi-quantitative Euroimmun IgG to viral spike S1 domain and Roche total antibody to viral nucleocapsid protein (NP) assays. Comparisons were made to pseudovirus neutralizing antibody measurements. Findings A total of 157/729 (21.5%) participants developed positive SARS-CoV-2 serology by one or other assay, of whom 31.0% were asymptomatic and there were no deaths. Peak Euroimmun anti-S1 and Roche anti-NP measurements correlated ( r = 0.57, p <0.0001) but only anti-S1 measurements correlated with near-contemporary pseudovirus neutralising antibody titres (measured at 16–18 weeks, r = 0.57, p <0.0001). By 21 weeks’ follow-up, 31/143 (21.7%) anti-S1 and 6/150 (4.0%) anti-NP measurements reverted to negative. Mathematical modelling revealed faster clearance of anti-S1 compared to anti-NP (median half-life of 2.5 weeks versus 4.0 weeks), earlier transition to lower levels of antibody production (median of 8 versus 13 weeks), and greater reductions in relative antibody production rate after the transition (median of 35% versus 50%). Interpretation Mild SARS-CoV-2 infection is associated with heterogeneous serological responses in Euroimmun anti-S1 and Roche anti-NP assays. Anti-S1 responses showed faster rates of clearance, more rapid transition from high to low level production rate and greater reduction in production rate after this transition. In mild infection, anti-S1 serology alone may underestimate incident infections. The mechanisms that underpin faster clearance and lower rates of sustained anti-S1 production may impact on the longevity of humoral immunity. Funding Charitable donations via Barts Charity, Wellcome Trust, NIHR.