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Over 80% of malaria-attributable deaths are in children under five. However, the only malaria vaccine recommended by the World Health Organization (WHO) for paediatric use, Mosquirix™, has limited efficacy. Complementary strategies, like monoclonal antibodies (mAbs), will be required to eradicate malaria. To discover new anti-malaria mAbs, we evaluated >28,000 antibody sequences from circulating B cells obtained from 45 Mosquirix™ vaccinees and selected 369 for testing. Many antibodies bound the circumsporozoite protein (CSP), a main surface protein on malaria and the malaria antigen in Mosquirix™, and several were exceptionally protective in mouse models of malaria. Through this work, we identified surprising correlations that suggest certain CSP sequences in Mosquirix™ may induce immunodominant antibody responses that dilute protective immunity. Further, we selected the antibodies most protective in preclinical mouse models and engineered them for improved manufacturability and developability to meet WHO guidelines. An optimised clinical candidate, MAM01, suitable for paediatric populations living in low-to-middle-income countries, was selected for clinical development.

Human immunodeficiency virus (HIV) is a mucosally transmitted virus that causes immunodeficiency and AIDS. Developing efficacious vaccines to prevent infection is essential to control the epidemic. Protecting the vaginal and rectal mucosa, the primary routes of HIV entry has been a challenge given the significant compartmentalization between the mucosal and peripheral immune systems. We hypothesized that direct intranodal vaccination of mucosa associated lymphoid tissue (MALT) such as the readily accessible palatine tonsils could overcome this compartmentalization. Here we show that rhesus macaques primed with plasmid DNA encoding SIVmac251-env and gag genes followed by an intranodal tonsil MALT boost with MVA encoding the same genes protects from a repeated low dose intrarectal challenge with highly pathogenic SIVmac251; 43% (3/7) of vaccinated macaques remained uninfected after 9 challenges as compared to the unvaccinated control (0/6) animals. One vaccinated animal remained free of infection even after 22 challenges. Vaccination was associated with a ~2 log decrease in acute viremia that inversely correlated with anamnestic immune responses. Our results suggest that a combination of systemic and intranodal tonsil MALT vaccination could induce robust adaptive and innate immune responses leading to protection from mucosal infection with highly pathogenic HIV and rapidly control viral breakthroughs.

Development of effective human immunodeficiency virus 1 (HIV-1) vaccines requires synergy between innate and adaptive immune cells. Here we show that induction of the transcription factor CREB1 and its target genes by the recombinant canarypox vector ALVAC + Alum augments immunogenicity in non-human primates (NHPs) and predicts reduced HIV-1 acquisition in the RV144 trial. These target genes include those encoding cytokines/chemokines associated with heightened protection from simian immunodeficiency virus challenge in NHPs. Expression of CREB1 target genes probably results from direct cGAMP (STING agonist)-modulated p-CREB1 activity that drives the recruitment of CD4