The proposed studies here will complement our studies in the P01 AI117915-06 “Early Life Vaccination to Prevent HIV Acquisition in Adolescence”. In the parent grant, we will define the molecular and immune pathways resulting in the induction of protective HIV Env-specific antibodies, both broadly neutralizing or Fc-mediated effector functions, in response to HIV Env SOSIP protein or HIV Env mRNA vaccination. Similar vaccine strategies are being pursued to combat the SARS-CoV-2 pandemic. The first human trial to test the immunogenicity of the mRNA encoding the stabilized prefusion Spike protein vaccine to prevent COVID-19 has been initiated. In contrast to the earlier outbreaks with the related coronaviruses, SARS and MERS, the SARS-CoV-2 exhibits enhanced transmissibility and has resulted in a pandemic. Globally, more than 2.5 million cases have been confirmed, with close to 750,000 deaths since the beginning of the outbreak. Infants infected with SARS, MERS, or SARS-CoV-2 appear to present with milder disease compared to adults, implying that that infants express fewer virus receptors, differ in host restriction factors, or that their immune system is better equipped to fight off these coronavirus strains. A vaccine is considered the best option to contain the virus and to prevent further outbreaks. For safety reasons, vaccine immunogenicity and safety are first evaluated in adults, yet a pediatric vaccine is preferable due to 1) the opportunity to generate protective immunity in childhood that will prevent disease throughout the lifespan and limit viral spread, and 2) high vaccine coverage is most easily obtained within the pediatric vaccine schedule. We are in the unique position to test already available candidate vaccines in parallel to adult trials in the pediatric setting. In experimental studies, neutralizing antibodies to the SARS or MERS virus spike (S) protein have proven to protect against virus infection. However, in humans recovering from SARS or MERS infections, antibody responses appear to be short lived. We hypothesize that infants can mount effective and persistent antibody responses to SARS-CoV-2 vaccination that will protect against virus challenge. Our rationale is based on our extensive data from human and rhesus macaque studies demonstrating that HIV Env vaccines induce plasma IgG antibodies (i) of comparable or higher magnitude to that of adults, (ii) that persist for months, and (iii) can be boosted, indicative of vaccine-induced memory. Our preliminary results with HIV Env SOSIP or mRNA vaccines confirm that these two novel vaccine strategies, if initiated at birth in rhesus macaques, can induce antibodies as efficiently as observed in adult macaques. We will test our hypothesis in the infant rhesus macaque model that has been proven to be of high translational value due to the similarities in physiology and immune development to that of human infants and the opportunity to assess systemic and local immune responses in the lung and lung-associated mucosal tissues.

Uncovering the immune responses that prevent SARS-CoV-2 replication and disease in pediatric populations is key to identify the appropriate age group for vaccines.