Reformulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines with variant strains is being pursued to combat the global surge in infections. We hypothesize that this may be ...suboptimal due to immune imprinting from earlier vaccination or infection with the original SARS-CoV-2 strain. New strategies may be needed to improve efficacy of SARS-CoV-2 variant vaccines.
•Recent advances in knowledge of blood and tissue T follicular helper cells.•Phenotype of responding cells influenced by vaccine or infection type.•Response magnitude influenced by antigen, ...microenvironment and age-specific factors.•Resolving heterogeneity in Tfh phenotype and function is key to improve vaccines.
T follicular helper (Tfh) cells are essential for the establishment, maintenance and output of the germinal centre (GC) response. The transient nature of this response, and its location within secondary lymphoid tissues have hampered our understanding of this critical cell type, particularly in humans. A counterpart of GC Tfh cells in peripheral blood has enabled recent discoveries in disease and vaccination settings, while direct sampling of lymph nodes provides exciting new avenues to study GC responses directly in vivo. Tfh differentiation is shaped by the cytokine milieu during inflammation, vaccination and with age, and disease-specific patterns are emerging. An improved understanding of how to support a Tfh response remains key to enhancing vaccine immunity across the lifespan.
...with the emergence and rapid global spread of the delta variant, it now seems likely that vaccination will not provide complete protection against acquisition and onward transmission of ...SARS-CoV-2, which will continue to circulate for the foreseeable future.5,6 Consequently, the goal of population-level vaccination has shifted to protecting both adults and children from developing severe disease, thereby preventing the excess mortality and stress on health-care systems that were observed in the early phases of the pandemic. Loss of neutralisation potency against the delta variant is not unique to the ChAdOx1 nCoV-19 vaccine; indeed, similar reductions have been reported using serum derived from cohorts vaccinated with mRNA vaccines.8,9 By contrast with antibody responses, the high frequency of spike-specific CD4 and CD8 T cells elicited by ChAdOx1 nCoV-19 vaccination maintained recognition of both wild-type and delta variant spike peptides. In a comprehensive analysis, Thiruvengadam and colleagues showed that both T-cell cytokine secretion and activation were comparable following stimulation with either wild-type or delta spike peptide pools.2 Considering the reduced antibody neutralisation but preserved T-cell recognition of the delta variant, these data raise the intriguing question of whether even low levels of neutralising antibodies are sufficient to prevent severe disease, or whether cellular immunity is a key factor in mitigating the risk of hospital admission.
The rapid development of multiple vaccines providing strong protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been a major achievement. There is now ...compelling evidence for the role of neutralizing antibodies in protective immunity. T cells may play a role in resolution of primary SARS-CoV-2 infection, and there is a widely expressed view that T cell-mediated immunity also plays an important role in vaccine-mediated protection. Here we discuss the role of vaccine-induced T cells in two distinct stages of infection: firstly, in protection from acquisition of symptomatic SARS-CoV-2 infection following exposure; secondly, if infection does occur, the potential for T cells to reduce the risk of developing severe COVID-19. We describe several lines of evidence that argue against a direct impact of vaccine-induced memory T cells in preventing symptomatic SARS-CoV-2 infection. However, the contribution of T cell immunity in reducing the severity of infection, particularly in infection with SARS-CoV-2 variants, remains to be determined. A detailed understanding of the role of T cells in COVID-19 is critical for next-generation vaccine design and development. Here we discuss the challenges in determining a causal relationship between vaccine-induced T cell immunity and protection from COVID-19 and propose an approach to gather the necessary evidence to clarify any role for vaccine-induced T cell memory in protection from severe COVID-19.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has dramatically expedited global vaccine development efforts
, most targeting the viral 'spike' glycoprotein (S). S ...localizes on the virion surface and mediates recognition of cellular receptor angiotensin-converting enzyme 2 (ACE2)
. Eliciting neutralizing antibodies that block S-ACE2 interaction
, or indirectly prevent membrane fusion
, constitute an attractive modality for vaccine-elicited protection
. However, although prototypic S-based vaccines show promise in animal models
, the immunogenic properties of S in humans are poorly resolved. In this study, we characterized humoral and circulating follicular helper T cell (cTFH) immunity against spike in recovered patients with coronavirus disease 2019 (COVID-19). We found that S-specific antibodies, memory B cells and cTFH are consistently elicited after SARS-CoV-2 infection, demarking robust humoral immunity and positively associated with plasma neutralizing activity. Comparatively low frequencies of B cells or cTFH specific for the receptor binding domain of S were elicited. Notably, the phenotype of S-specific cTFH differentiated subjects with potent neutralizing responses, providing a potential biomarker of potency for S-based vaccines entering the clinic. Overall, although patients who recovered from COVID-19 displayed multiple hallmarks of effective immune recognition of S, the wide spectrum of neutralizing activity observed suggests that vaccines might require strategies to selectively target the most potent neutralizing epitopes.
Humans commonly have low level antibodies to poly(ethylene) glycol (PEG) due to environmental exposure. Lipid nanoparticle (LNP) mRNA vaccines for SARS-CoV-2 contain small amounts of PEG, but it is ...not known whether PEG antibodies are enhanced by vaccination and what their impact is on particle–immune cell interactions in human blood. We studied plasma from 130 adults receiving either the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) mRNA vaccines or no SARS-CoV-2 vaccine for PEG-specific antibodies. Anti-PEG IgG was commonly detected prior to vaccination and was significantly boosted a mean of 13.1-fold (range 1.0–70.9) following mRNA-1273 vaccination and a mean of 1.78-fold (range 0.68–16.6) following BNT162b2 vaccination. Anti-PEG IgM increased 68.5-fold (range 0.9–377.1) and 2.64-fold (0.76–12.84) following mRNA-1273 and BNT162b2 vaccination, respectively. The rise in PEG-specific antibodies following mRNA-1273 vaccination was associated with a significant increase in the association of clinically relevant PEGylated LNPs with blood phagocytes ex vivo. PEG antibodies did not impact the SARS-CoV-2 specific neutralizing antibody response to vaccination. However, the elevated levels of vaccine-induced anti-PEG antibodies correlated with increased systemic reactogenicity following two doses of vaccination. We conclude that PEG-specific antibodies can be boosted by LNP mRNA vaccination and that the rise in PEG-specific antibodies is associated with systemic reactogenicity and an increase of PEG particle–leukocyte association in human blood. The longer-term clinical impact of the increase in PEG-specific antibodies induced by lipid nanoparticle mRNA vaccines should be monitored. It may be useful to identify suitable alternatives to PEG for developing next-generation LNP vaccines to overcome PEG immunogenicity in the future.
Vaccination remains the most effective mechanism to reduce the impact of COVID‐19. Induction of neutralizing antibodies is a strong correlate of protection from infection and severe disease. An ...understanding of the cellular events that underpin the generation of effective neutralizing antibodies is therefore key to the development of efficacious vaccines that target emerging variants of concern. Analysis of the immune response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) infection and vaccination has identified circulating T follicular helper cells (cTFH) as a robust correlate of the neutralizing antibody response. Here, we discuss the analysis of cTFH cells and their lymphoid counterparts in human humoral immune responses during COVID‐19, and in response to vaccination with SARS‐CoV‐2 spike. We discuss the phenotypic heterogeneity of cTFH cells and the utility of cTFH subsets as informative biomarkers for development of humoral immunity. We posit that the analysis of the most effective cTFH will be critical to inducing durable immunity to new variants of SARS‐CoV‐2.
Graphical
Review on the analysis of TFH cells during COVID‐19 infection and vaccination and the role of these cells as biomarkers of neutralising antibody development.
Mucosal-associated invariant T (MAIT) cells can recognize and respond to some bacterially infected cells. Several in vitro and in vivo models of Mycobacterium tuberculosis (Mtb) infection suggest ...that MAIT cells can contribute to control of Mtb, but these studies are often cross-sectional and use peripheral blood cells. Whether MAIT cells are recruited to Mtb-affected granulomas and lymph nodes (LNs) during early Mtb infection and what purpose they might serve there is less well understood. Furthermore, whether HIV/SIV infection impairs MAIT cell frequency or function at the sites of Mtb replication has not been determined. Using Mauritian cynomolgus macaques (MCM), we phenotyped MAIT cells in the peripheral blood and bronchoalveolar lavage (BAL) before and during infection with SIVmac239. To test the hypothesis that SIV co-infection impairs MAIT cell frequency and function within granulomas, SIV+ and -naïve MCM were infected with a low dose of Mtb Erdman, and necropsied at 6 weeks post Mtb-challenge. MAIT cell frequency and function were examined within the peripheral blood, BAL, and Mtb-affected lymph nodes (LN) and granulomas. MAIT cells did not express markers indicative of T cell activation in response to Mtb in vivo within granulomas in animals infected with Mtb alone. SIV and Mtb co-infection led to increased expression of the activation/exhaustion markers PD-1 and TIGIT, and decreased ability to secrete TNFα when compared to SIV-naïve MCM. Our study provides evidence that SIV infection does not prohibit the recruitment of MAIT cells to sites of Mtb infection, but does functionally impair those MAIT cells. Their impaired function could have impacts, either direct or indirect, on the long-term containment of TB disease.
Elimination of the latent HIV reservoir remains a major barrier to achieving an HIV cure. In this review, we discuss the cytolytic nature of human gamma delta T cells and highlight the emerging ...evidence that they can target and eliminate HIV-infected T cells. Based on observations from human clinical trials assessing gamma delta immunotherapy in oncology, we suggest key questions and research priorities for the study of these unique T cells in HIV cure research.
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