Vaccines have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) morbidity and mortality, yet emerging variants challenge their effectiveness. The prevailing approach to updating vaccines targets the antibody response, operating under the presumption that it is the primary defense mechanism following vaccination or infection. This perspective, however, can overlook the role of T cells, particularly when antibody levels are low or absent. Here we show, through studies in mouse models lacking antibodies but maintaining functional B cells and lymphoid organs, that immunity conferred by prior infection or mRNA vaccination can protect against SARS-CoV-2 challenge independently of antibodies. Our findings, using three distinct models inclusive of a novel human/mouse ACE2 hybrid, highlight that CD8+ T cells are essential for combating severe infections, whereas CD4+ T cells contribute to managing milder cases, with interferon-γ having an important function in this antibody-independent defense. These findings highlight the importance of T cell responses in vaccine development, urging a broader perspective on protective immunity beyond just antibodies.

Engagement of the receptor programmed cell death molecule 1 (PD-1) by its ligands PD-L1 and PD-L2 inhibits T cell–mediated immune responses. Blocking such signaling provides the clinical effects of PD-1–targeted immunotherapy. Here, we investigated the mechanisms underlying PD-1–mediated inhibition. Because dynamic actin remodeling is crucial for T cell functions, we characterized the effects of PD-1 engagement on actin remodeling at the immunological synapse, the interface between a T cell and an antigen-presenting cell (APC) or target cell. We used microscopy to analyze the formation of immunological synapses between PD-1 + Jurkat cells or primary human CD8 + cytotoxic T cells and APCs that presented T cell–activating antibodies and were either positive or negative for PD-L1. PD-1 binding to PD-L1 inhibited T cell spreading induced by antibody-mediated activation, which was characterized by the absence of the F-actin–dense distal lamellipodial network at the immunological synapse and the Arp2/3 complex, which mediates branched actin formation. PD-1–induced inhibition of actin remodeling also prevented the characteristic deformation of T cells that contact APCs and the release of cytotoxic granules. We showed that the effects of PD-1 on actin remodeling did not require its tyrosine-based signaling motifs, which are thought to mediate the co-inhibitory effects of PD-1. Our study highlights a previously unappreciated mechanism of PD-1–mediated suppression of T cell activity, which depends on the regulation of actin cytoskeleton dynamics in a signaling motif–independent manner.

The development and deployment of vaccines against COVID-19 demonstrated major successes in providing immunity and preventing severe disease and death. Yet SARS-CoV-2 evolves and vaccine-induced protection wanes, meaning progress in vaccination strategies is of upmost importance. New vaccines directed at emerging viral strains are being developed while vaccination schemes with booster doses and combinations of different platform-based vaccines are being tested in trials and real-world settings. Despite these diverse approaches, COVID-19 vaccines are only delivered intramuscularly, whereas the nasal mucosa is the primary site of infection with SARS-CoV-2. Preclinical mucosal vaccines with intranasal or oral administration demonstrate promising results regarding mucosal IgA generation and tissue-resident lymphocyte responses against SARS-CoV-2. By mounting an improved local humoral and cell-mediated response, mucosal vaccination could be a safe and effective way to prevent infection, block transmission and contribute to reduce SARS-CoV-2 spread. However, questions and limitations remain: how effectively and reproducibly will vaccines penetrate mucosal barriers? Will vaccine-induced mucosal IgA responses provide sustained protection against infection?

With the elevated transmissibility of circulating SARS-CoV-2 variants, vaccination coverages as high as 90% in adults might be necessary to fully relax control measures towards the end of 2021.1Tran Kiem C, Massonnaud C, Levy-Bruhl D, et al. Short and medium-term challenges for COVID-19 vaccination: from prioritisation to the relaxation of measures. EClinicalMedicine (in press).Google Scholar Such targets might be hard to reach because of vaccine hesitancy. Therefore, there is a risk that COVID-19 might cause substantial stress on health care in the winter months at the end of 2021 and beginning of 2022. Modelling data suggest that vaccination of children and adolescents could help mitigate this risk of SARS-CoV-2 dissemination by ensuring they do not act as a reservoir.1Tran Kiem C, Massonnaud C, Levy-Bruhl D, et al. Short and medium-term challenges for COVID-19 vaccination: from prioritisation to the relaxation of measures. EClinicalMedicine (in press).Google Scholar However, since COVID-19 is mild in children,2Hoang A Chorath K Moreira A et al.COVID-19 in 7780 pediatric patients: a systematic review.EClinicalMedicine. 2020; 24100433Summary Full Text Full Text PDF PubMed Scopus (401) Google Scholar such intervention might be ethically problematic if the population benefits come without individual benefits for children. Here, we argue that vaccinating children and adolescents is important to secure their continued access to education and protect their mental health. In the event of a COVID-19 epidemic rebound during the winter months, we anticipate that control strategies will evolve to preferably target unvaccinated individuals, accounting for the reduced contribution of vaccinated individuals to disease spread. Living with children aged 11–17 years increases the risk of SARS-CoV-2 infection by 18–30%.3Galmiche S Charmet T Schaeffer L et al.Exposures associated with SARS-CoV-2 infection in France: a nationwide online case-control study.Lancet Reg Health Eur. 2021; 7100148Summary Full Text Full Text PDF PubMed Scopus (61) Google Scholar This contribution to disease spread could substantially increase once children are the only unvaccinated group, leading to a larger proportion of infections and clusters occurring in schools. Although such clusters might be tolerated if the rate of admission to hospital remains low, there is a point beyond which class closures might be reinstated. These closures would be highly detrimental to the education and wellbeing of children and adolescents who have had their schooling increasingly disrupted.4YoungMindsCoronavirus: impact on young people with mental health needs. YoungMinds, London2021Google Scholar School closure can affect learning, lead to anxiety and depressive symptoms, exacerbate tensions or even intrafamily violence, and deepen social inequalities. Early data from clinical trials suggest that the BNT162b2 mRNA COVID-19 vaccine (Pfizer–BioNTech) is safe and highly immunogenic in adolescents aged 12–15 years.5Frenck RW Klein NP Kitchin N et al.Safety, immunogenicity, and efficacy of the BNT162b2 COVID-19 vaccine in adolescents.New Engl J Med. 2021; (published online May 27.)https://doi.org/10.1056/NEJMoa2107456Crossref PubMed Scopus (629) Google Scholar On May 10, 2021, the US Food and Drug Administration, followed by the European Medicines Agency on May 28, 2021, extended the use of this vaccine to include adolescents aged 12–15 years. Side-effects in vaccinated adolescents should be carefully monitored at population level to make sure that rare but severe side-effects will not go unnoticed. As data from ongoing trials in children younger than 12 years become available, vaccination in younger age groups could be considered. At a time when we all want to return to normal life, we cannot ignore the fact that children share the same aspirations. The vaccination of children against COVID-19 would be the best way to insulate them from the risk of class closures, secure their continued access to education, and protect their mental health. We declare funding from Investissement d'Avenir programme, the Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases programme, and the EU's Horizon 2020 research and innovation programme. The funders had no role in the writing of or decision to submit this Correspondence.