Short-Lived IFN-γ Effector Responses, but Long-Lived IL-10 Memory Responses, to Malaria in an Area of Low Malaria Endemicity

Immunity to malaria is widely believed to wane in the absence of reinfection, but direct evidence for the presence or absence of durable immunological memory to malaria is limited. Here, we analysed malaria-specific CD4+ T cell responses of individuals living in an area of low malaria transmission in northern Thailand, who had had a documented clinical attack of P. falciparum and/or P. vivax in the past 6 years. CD4+ T cell effector memory (CD45RO+) IFN-γ (24 hours ex vivo restimulation) and cultured IL-10 (6 day secretion into culture supernatant) responses to malaria schizont antigens were detected only in malaria-exposed subjects and were more prominent in subjects with long-lived antibodies or memory B cells specific to malaria antigens. The number of IFN-γ-producing effector memory T cells declined significantly over the 12 months of the study, and with time since last documented malaria infection, with an estimated half life of the response of 3.3 (95% CI 1.9–10.3) years. In sharp contrast, IL-10 responses were sustained for many years after last known malaria infection with no significant decline over at least 6 years. The observations have clear implications for understanding the immunoepidemiology of naturally acquired malaria infections and for malaria vaccine development

Structural analysis of a dengue cross-reactive antibody complexed with envelope domain III reveals the molecular basis of cross-reactivity.

Dengue virus infections are still increasing at an alarming rate in tropical and subtropical countries, underlying the need for a dengue vaccine. Although it is relatively easy to generate Ab responses to dengue virus, low avidity or low concentrations of Ab may enhance infection of FcR-bearing cells with clinical impact, posing a challenge to vaccine production. In this article, we report the characterization of a mAb, 2H12, which is cross-reactive to all four serotypes in the dengue virus group. Crystal structures of 2H12-Fab in complex with domain III of the envelope protein from three dengue serotypes have been determined. 2H12 binds to the highly conserved AB loop of domain III of the envelope protein that is poorly accessible in the mature virion. 2H12 neutralization varied between dengue serotypes and strains; in particular, dengue serotype 2 was not neutralized. Because the 2H12-binding epitope was conserved, this variation in neutralization highlights differences between dengue serotypes and suggests that significant conformational changes in the virus must take place for Ab binding. Surprisingly, 2H12 facilitated little or no enhancement of infection. These data provide a structural basis for understanding Ab neutralization and enhancement of infection, which is crucial for the development of future dengue vaccines

Cross-Reacting Antibodies Enhance Dengue Virus Infection in Humans

Dengue virus co-circulates as four serotypes and sequential infections with more than one serotype are common. One hypothesis for the increased severity seen in secondary infections is antibody dependent enhancement (ADE) leading to increased replication in Fc-receptor-bearing cells. In this study we have generated a panel of human monoclonal antibodies to dengue virus. Antibodies to the structural precursor-membrane protein (prM) dominate the response. These antibodies are highly cross-reactive among the dengue virus serotypes and, even at high concentrations, do not neutralise infection but potently promote ADE. We propose that the partial cleavage of prM from the viral surface reduces the density of antigen available for viral neutralisation, leaving dengue viruses susceptible to ADE by anti-prM, a finding which has implications for future vaccine design

Characterization of a potent and highly unusual minimally enhancing antibody directed against dengue virus

Dengue virus is a major pathogen and severe infections can lead to life threatening dengue hemorrhagic fever (DHF). Dengue exists as four serotypes and DHF is often associated with secondary heterologous infections. Antibody dependent enhancement (ADE) may drive higher virus loads in these secondary infections, and is purported to result from antibodies that recognize dengue but fail to fully neutralize. We have characterized two antibodies, 2C8 and 3H5, which bind to the envelope protein. 3H5 is highly unusual as it is both potently neutralizing, but promotes little if any ADE, whereas 2C8 has strong capacity to promote ADE. We show that 3H5 shows resilient binding in endosomal pH conditions and neutralizes at low occupancy. Immune complexes of 3H5 and dengue virus do not efficiently interact with Fcγ receptors, which we propose is due to the binding mode of 3H5 and which constitutes the primary mechanism of how ADE is avoided

Characterization of a potent and highly unusual minimally enhancing antibody directed against dengue virus

Dengue virus is a major pathogen and severe infections can lead to life threatening dengue hemorrhagic fever (DHF). Dengue exists as four serotypes and DHF is often associated with secondary heterologous infections. Antibody dependent enhancement (ADE) may drive higher virus loads in these secondary infections, and is purported to result from antibodies that recognize dengue but fail to fully neutralize. We have characterized two antibodies, 2C8 and 3H5, which bind to the envelope protein. 3H5 is highly unusual as it is both potently neutralizing, but promotes little if any ADE, whereas 2C8 has strong capacity to promote ADE. We show that 3H5 shows resilient binding in endosomal pH conditions and neutralizes at low occupancy. Immune complexes of 3H5 and dengue virus do not efficiently interact with Fcγ receptors, which we propose is due to the binding mode of 3H5 and which constitutes the primary mechanism of how ADE is avoided

Characterization of a potent and highly unusual minimally enhancing antibody directed against dengue virus

Dengue virus is a major pathogen and severe infections can lead to life threatening dengue hemorrhagic fever (DHF). Dengue exists as four serotypes and DHF is often associated with secondary heterologous infections. Antibody dependent enhancement (ADE) may drive higher virus loads in these secondary infections, and is purported to result from antibodies that recognize dengue but fail to fully neutralize. We have characterized two antibodies, 2C8 and 3H5, which bind to the envelope protein. 3H5 is highly unusual as it is both potently neutralizing, but promotes little if any ADE, whereas 2C8 has strong capacity to promote ADE. We show that 3H5 shows resilient binding in endosomal pH conditions and neutralizes at low occupancy. Immune complexes of 3H5 and dengue virus do not efficiently interact with Fcγ receptors, which we propose is due to the binding mode of 3H5 and which constitutes the primary mechanism of how ADE is avoided