BackgroundThe efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction of responses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccine designs are largely based on viral sequence alignments only, not incorporating experimental data on T cell function and specificity.MethodsHere, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410 overlapping peptides (OLP) spanning the entire HIV-1 proteome. For each OLP, a "protective ratio" (PR) was calculated as the ratio of median viral loads (VL) between OLP non-responders and responders.ResultsFor both clades, there was a negative relationship between the PR and the entropy of the OLP sequence. There was also a significant additive effect of multiple responses to beneficial OLP. Responses to beneficial OLP were of significantly higher functional avidity than responses to non-beneficial OLP. They also had superior in-vitro antiviral activities and, importantly, were at least as predictive of individuals' viral loads than their HLA class I genotypes.ConclusionsThe data thus identify immunogen sequence candidates for HIV and provide an approach for T cell immunogen design applicable to other viral infections.
Studies
of two SARS-CoV-2 mRNA vaccines suggested that they yield
∼95% protection from symptomatic infection at least short-term,
but important clinical questions remain. It is unclear how vaccine-induced
antibody levels quantitatively compare to the wide spectrum induced
by natural SARS-CoV-2 infection. Vaccine response kinetics and magnitudes
in persons with prior COVID-19 compared to virus-naı̈ve
persons are not well-defined. The relative stability of vaccine-induced
versus infection-induced antibody levels is unclear. We addressed
these issues with longitudinal assessments of vaccinees with and without
prior SARS-CoV-2 infection using quantitative enzyme-linked immunosorbent
assay (ELISA) of anti-RBD antibodies. SARS-CoV-2-naı̈ve
individuals achieved levels similar to mild natural infection after
the first vaccination; a second dose generated levels approaching
severe natural infection. In persons with prior COVID-19, one dose
boosted levels to the high end of severe natural infection even in
those who never had robust responses from infection, increasing no
further after the second dose. Antiviral neutralizing assessments
using a spike-pseudovirus assay revealed that virus-naı̈ve
vaccinees did not develop physiologic neutralizing potency until the
second dose, while previously infected persons exhibited maximal neutralization
after one dose. Finally, antibodies from vaccination waned similarly
to natural infection, resulting in an average of ∼90% loss
within 90 days. In summary, our findings suggest that two doses are
important for quantity and quality of humoral immunity in SARS-CoV-2-naı̈ve persons, while
a single dose has maximal effects in those with past infection. Antibodies
from vaccination wane with kinetics very similar to that seen after
mild natural infection; booster vaccinations will likely be required.
While pregnancy increases the risk for severe COVID19, the clinical and immunological implications of COVID19 on maternal-fetal health remain unknown. Here, we present the clinical and immunological landscapes of 93 COVID19 mothers and 45 of their SARS-CoV-2-exposed infants through comprehensive serum proteomics profiling for >1400 cytokines of their peripheral and cord blood specimens. Prenatal SARS-CoV-2 infection triggers NF-κB-dependent proinflammatory immune activation. Pregnant women with severe COVID19 show increased inflammation and unique IFNλ antiviral signaling, with elevated levels of IFNL1 and IFNLR1. Furthermore, SARS-CoV-2 infection re-shapes maternal immunity at delivery altering the expression of pregnancy complication-associated cytokines, inducing MMP7, MDK, ESM1, and reducing BGN and CD209. Finally, COVID19-exposed infants exhibit induction of T cell-associated cytokines (IL33, NFATC3 and CCL21), while some undergo IL-1β/IL-18/CASP1 axis-driven neonatal respiratory distress despite birth at term. Our findings demonstrate COVID19-induced immune rewiring in both mothers and neonates, warranting long-term clinical follow-up to mitigate potential health risks.
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