ABSTRACT
People living with HIV (PLWH) on suppressive antiretroviral therapy (ART) can have residual immune dysfunction and often display poorer responses to vaccination. We assessed in a cohort of PLWH (n=110) and HIV negative controls (n=64) the humoral and spike-specific B-cell responses following 1, 2 or 3 SARS-CoV-2 vaccine doses. PLWH had significantly lower neutralizing antibody (nAb) titers than HIV-negative controls at all studied timepoints. Moreover, their neutralization breadth was reduced with fewer individuals developing a neutralizing response against the Omicron variant (BA.1) relative to controls. We also observed a delayed development of neutralization in PLWH that was underpinned by a reduced frequency of spike-specific memory B cells (MBCs) and pronounced B cell dysfunction. Improved neutralization breadth was seen after the third vaccine dose in PLWH but lower nAb responses persisted and were associated with global, but not spike-specific, MBC dysfunction. In contrast to the inferior antibody responses, SARS-CoV-2 vaccination induced robust T cell responses that cross-recognized variants in PLWH. Strikingly, a subset of PLWH with low or absent neutralization had detectable functional T cell responses. These individuals had reduced numbers of circulating T follicular helper cells and an enriched population of CXCR3+CD127+CD8+ T cells after two doses of SARS-CoV-2 vaccination, which may compensate for sub-optimal serological responses in the event of infection. Therefore, normalisation of B cell homeostasis could improve serological responses to vaccines in PLWH and evaluating T cell immunity could provide a more comprehensive immune status profile in these individuals and others with B cell imbalances.
ABSTRACT
Although over 12 billion COVID-19 vaccine doses have been administered globally, the important issue of whether the optimal doses are being used has been relatively neglected. To address this question, we reviewed the reports of early-phase dose-finding trials of the nine COVID-19 vaccines approved by World Health Organization (and one additional vaccine which showed partial clinical efficacy), extracting information on study design and findings on reactogenicity and early humoral immune response. The number of different doses evaluated per vaccine varied widely (range 1-7), as did the number of subjects studied per dose (range 15-190). As expected, the frequency and severity of adverse reactions generally increased at higher doses, although most were clinically tolerable. Higher doses also tended to elicit better immune responses, but differences between the maximum dose and the second-highest dose evaluated were small, typically less than 1.6-fold for both binding antibody concentration and neutralising antibody titre. All of the trials had at least one important design limitation: few doses evaluated, large gaps between adjacent doses, or an inadequate sample size. In general, it is therefore uncertain whether the single dose taken into clinical efficacy trials, and subsequently authorised by regulatory agencies, was optimal. In particular, the recommended doses for some vaccines appear to be unnecessarily high. Although reduced dosing for booster injections is an active area of research, the priming dose is equally deserving of study. We conclude by suggesting some ways in which the design of future trials of candidate COVID-19 vaccines could be improved.
ABSTRACT
BackgroundAlthough SARS-CoV-2 infection in Healthcare Workers (HCWs) is a public health concern, there is little description of their longitudinal antibody response in the presence or absence of SARS-CoV-2 and symptoms. We followed HCWs in an acute London hospital to measure seroconversion and RNA detection at the peak of the pandemic. MethodsWe enrolled 200 patient-facing HCWs between 26 March and 8 April 2020 and collected twice-weekly self-administered nose and throat swabs, symptom data and monthly blood samples. Swabs were tested for SARS-CoV-2 by PCR, and serum for antibodies to spike protein by ELISA and flow cytometry. FindingsDuring the first month, 42/200 (21%) HCWs were PCR positive in at least one nose and throat swab. Only 8/42 HCW (19%) who were PCR positive during the study period had symptoms that met current case definition. Of 181 HCWs who provided enrollment and follow-up blood samples, 82/181 (45.3%) were seropositive. In 33 HCWs who had positive serology at baseline but were PCR negative, 32 remained PCR negative. One HCW had a PCR positive swab six days after enrollment, likely representing waning infection. ConclusionThe high seropositivity and RNA detection in these front-line HCWs brings policies to protect staff and patients into acute focus. Our findings have implications for planning for the second wave and for vaccination campaigns in similar settings. The evidence of asymptomatic SARS-CoV-2 infection indicates that asymptomatic HCW surveillance is essential, while our study sets the foundations to answer pertinent questions around the duration of protective immune response and the risk of re-infection.
