RESUMEN
The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against the disease-causing blood stage of malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here, we characterize 236 human IgG monoclonal antibodies, derived from 15 donors, induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule and establish that epitope specificity, antibody association rate, and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline IgG gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria.
Asunto(s)
Anticuerpos Monoclonales , Anticuerpos Antiprotozoarios , Antígenos de Protozoos , Inmunoglobulina G , Vacunas contra la Malaria , Malaria Falciparum , Plasmodium falciparum , Proteínas Protozoarias , Animales , Humanos , Ratones , Anticuerpos Monoclonales/inmunología , Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/inmunología , Proteínas Portadoras/inmunología , Epítopos/inmunología , Eritrocitos/parasitología , Eritrocitos/inmunología , Inmunoglobulina G/inmunología , Vacunas contra la Malaria/inmunología , Malaria Falciparum/inmunología , Malaria Falciparum/prevención & control , Malaria Falciparum/parasitología , Plasmodium falciparum/inmunología , Proteínas Protozoarias/inmunologíaRESUMEN
Lyme arthritis, caused by the spirochete Borrelia burgdorferi, is the most common feature of late disseminated Lyme disease in the United States. While most Lyme arthritis resolves with antibiotics, termed "antibiotic-responsive", some individuals develop progressive synovitis despite antibiotic therapy, called "antibiotic-refractory" Lyme arthritis (LA). The primary drivers behind antibiotic-refractory arthritis remain incompletely understood. We performed a matched, cross-compartmental comparison of antibody profiles from blood and joint fluid of individuals with antibiotic-responsive (n = 11) or antibiotic-refractory LA (n = 31). While serum antibody profiles poorly discriminated responsive from refractory patients, a discrete profile of B.burgdorferi-specific antibodies in joint fluid discriminated antibiotic-responsive from refractory LA. Cross-compartmental comparison of antibody glycosylation, IgA1, and antibody-dependent complement deposition (ADCD) revealed more poorly coordinated humoral responses and increased ADCD in refractory disease. These data reveal B.burgdorferi-specific serological markers that may support early stratification and clinical management, and point to antibody-dependent complement activation as a key mechanism underlying persistent disease.