A targeted single mutation in influenza A virus universal epitope transforms immunogenicity and protective immunity via CD4+ T cell activation.

CD4+ T cells are central to adaptive immunity. Their role in cross-protection in viral infections such as influenza and severe acute respiratory syndrome (SARS) is well documented; however, molecular rules governing T cell receptor (TCR) engagement of peptide-human leukocyte antigen (pHLA) class II are less understood. Here, we exploit an aspect of HLA class II presentation, the peptide-flanking residues (PFRs), to "tune" CD4+ T cell responses within an in vivo model system of influenza. Using a recombinant virus containing targeted substitutions at immunodominant HLA-DR1 epitopes, we demonstrate limited weight loss and improved clinical scores after heterosubtypic re-challenge. We observe enhanced protection linked to lung-derived influenza-specific CD4+ and CD8+ T cells prior to re-infection. Structural analysis of the ternary TCR:pHLA complex identifies that flanking amino acids influence side chains in the core 9-mer peptide, increasing TCR affinity. Augmentation of CD4+ T cell immunity is achievable with a single mutation, representing a strategy to enhance adaptive immunity that is decoupled from vaccine modality.

Open science communication: The first year of the UK's Independent Scientific Advisory Group for Emergencies.

The COVID-19 pandemic has shone a light on the complex relationship between science and policy. Policymakers have had to make decisions at speed in conditions of uncertainty, implementing policies that have had profound consequences for people's lives. Yet this process has sometimes been characterised by fragmentation, opacity and a disconnect between evidence and policy. In the United Kingdom, concerns about the secrecy that initially surrounded this process led to the creation of Independent SAGE, an unofficial group of scientists from different disciplines that came together to ask policy-relevant questions, review the evolving evidence, and make evidence-based recommendations. The group took a public health approach with a population perspective, worked in a holistic transdisciplinary way, and were committed to public engagement. In this paper, we review the lessons learned during its first year. These include the importance of learning from local expertise, the value of learning from other countries, the role of civil society as a critical friend to government, finding appropriate relationships between science and policy, and recognising the necessity of viewing issues through an equity lens.

Proteome-Wide Zika Virus CD4 T Cell Epitope and HLA Restriction Determination.

Zika virus (ZIKV) is a mosquito-borne pathogen that caused an epidemic in 2015-2016. ZIKV-specific T cell responses are functional in animal infection models, and helper CD4 T cells promote avid Abs in the vaccine context. The small volumes of blood available from field research limit the determination of T cell epitopes for complex microbes such as ZIKV. The goal of this project was efficient determination of human ZIKV CD4 T cell epitopes at the whole proteome scale, including validation of reactivity to whole pathogen, using small blood samples from convalescent time points when T cell response magnitude may have waned. Polyclonal enrichment of candidate ZIKV-specific CD4 T cells used cell-associated virus, documenting that T cells in downstream peptide analyses also recognize whole virus after Ag processing. Sequential query of bulk ZIKV-reactive CD4 T cells with pooled/single ZIKV peptides and molecularly defined APC allowed precision epitope and HLA restriction assignments across the ZIKV proteome and enabled discovery of numerous novel ZIKV CD4 T cell epitopes. The research workflow is useful for the study of emerging infectious diseases with a very limited human blood sample availability.

Priorities for research on meningococcal disease and the impact of serogroup A vaccination in the African meningitis belt.

For over 100 years, large epidemics of meningococcal meningitis have occurred every few years in areas of the African Sahel and sub-Sahel known as the African meningitis belt. Until recently, the main approach to the control of these epidemics has been reactive vaccination with a polysaccharide vaccine after an outbreak has reached a defined threshold and provision of easy access to effective treatment but this approach has not prevented the occurrence of new epidemics. Meningococcal conjugate vaccines, which can prevent meningococcal carriage and thus interrupt transmission, may be more effective than polysaccharide vaccines at preventing epidemics. Because the majority of African epidemics have been caused by serogroup A meningococci, a serogroup A polysaccharide/tetanus toxoid protein conjugate vaccine (PsA-TT) has recently been developed. Results from an initial evaluation of the impact of this vaccine on meningococcal disease and meningococcal carriage in Burkina Faso have been encouraging. To review how the research agenda for meningococcal disease in Africa has been changed by the advent of PsA-TT and to define a new set of research priorities for study of meningococcal infection in Africa, a meeting of 41 scientists was held in Dakar, Senegal on April 24th and 25th 2012. The research recommendations developed during the course of this meeting are presented in this paper. The need for enhanced surveillance for meningitis in defined populations with good diagnostic facilities in African countries at risk of epidemics was identified as the highest priority. This is needed to determine the duration of protection against serogroup A meningococcal disease provided by PsA-TT and to determine the risk of disease and carriage caused by meningococci of other serogroups. Other research areas given high priority included identification and validation of serological correlates of protection against meningococcal disease and carriage, development of improved methods for detecting carriage and epidemiological studies aimed at determining the reasons underlying the peculiar epidemiology of meningococcal disease in the African meningitis belt. Minutes and working papers from the meeting are provided in supplementary tables and some of the presentations made at the meeting are available on the MenAfriCar consortium website (www.menafricar.org) and on the web site of the Centers for Disease Control (www.cdc.gov).

Detection and treatment of subclinical tuberculosis.

Reduction of active disease by preventive therapy has the potential to make an important contribution towards the goal of tuberculosis (TB) elimination. This report summarises discussions amongst a Working Group convened to consider areas of research that will be important in optimising the design and delivery of preventative therapies. The Working Group met in Cape Town on 26th February 2012, following presentation of results from the GC11 Grand Challenges in Global Health project to discover drugs for latent TB.

An anthrax subunit vaccine candidate based on protective regions of Bacillus anthracis protective antigen and lethal factor.

Studies have confirmed the key role of Bacillus anthracis protective antigen (PA) in the US and UK human anthrax vaccines. However, given the tripartite nature of the toxin, other components, including lethal factor (LF), are also likely to contribute to protection. We examined the antibody and T cell responses to PA and LF in human volunteers immunized with the UK anthrax vaccine (AVP). Individual LF domains were assessed for immunogenicity in mice when given alone or with PA. Based on the results obtained, a novel fusion protein comprising D1 of LF and the host cell-binding domain of PA (D4) was assessed for protective efficacy. Murine protection studies demonstrated that both full-length LF and D1 of LF conferred complete protection against a lethal intraperitoneal challenge with B. anthracis STI spores. Subsequent studies with the LFD1-PAD4 fusion protein showed a similar level of protection. LF is immunogenic in humans and is likely to contribute to the protection stimulated by AVP. A single vaccine comprising protective regions from LF and PA would simplify production and confer a broader spectrum of protection than that seen with PA alone.