Potential solution(s)

Understanding how immunity develops • Poor immunogenicity and/or durability • Lack of correlates of protection • Inefficient activation of innate immunity • Lack of animal models with predictive value

Systems biology studies Identify non-humoral correlates of protection Better understanding of the effector functions associated with spontaneous resolution of infection Vaccines inducing cellular immunity Laboratory assays measuring functional responses correlated with clinical protection

Host variability • Inter-individual variability in vaccine response • Non-responder populations • Sex, age, race, ethnic differences in response

Age, sex, or population-based vaccine formulations Diagnostic tests to predict vaccine response

Pathogen variability • Pathogen diversity • Antigenic drift and antigenic shift • Hypervariable viruses • Complex biology (e.g., Plasmodium) • Active vs. latent vs. chronic infection • Host pathogen interactions • Immune response evasion mutants

Vaccines eliciting broadly neutralizing Abs Multi-valent vaccines eliciting high affinity Ab to multiple serotypes Universal vaccine based on genetically conserved epitopes Vaccines targeting pre-erythrocytic, blood, and/or mosquito stages Interventions that mitigate pathogen immunomodulation during immune response to vaccination DNA vaccine targeting T cell responses to the partially conserved NS3 and C genes and Ab responses to the E protein

Vaccine safety • Adverse events • Autoimmunity • Vaccine hesitancy

Subunit, protein, and peptide-based vaccines incorporating novel adjuvants driving immunogenicity and durable protection Dose-sparing approaches

Environmental and geographic factors • Poor nutrition/obesity • Co-infection • Prior immunity • Pollution

DENV-vaccines for naïve and DENV-exposed individuals Vitamin supplementation coadministered with vaccination