Date Published: July 19, 2016
Publisher: Public Library of Science
Author(s): Cecilia Rademeyer, Bette Korber, Michael S. Seaman, Elena E. Giorgi, Ruwayhida Thebus, Alexander Robles, Daniel J. Sheward, Kshitij Wagh, Jetta Garrity, Brittany R. Carey, Hongmei Gao, Kelli M. Greene, Haili Tang, Gama P. Bandawe, Jinny C. Marais, Thabo E. Diphoko, Peter Hraber, Nancy Tumba, Penny L. Moore, Glenda E. Gray, James Kublin, M. Juliana McElrath, Marion Vermeulen, Keren Middelkoop, Linda-Gail Bekker, Michael Hoelscher, Leonard Maboko, Joseph Makhema, Merlin L. Robb, Salim Abdool Karim, Quarraisha Abdool Karim, Jerome H. Kim, Beatrice H. Hahn, Feng Gao, Ronald Swanstrom, Lynn Morris, David C. Montefiori, Carolyn Williamson, Richard A. Koup.
The development of biomedical interventions to reduce acquisition of HIV-1 infection remains a global priority, however their potential effectiveness is challenged by very high HIV-1 envelope diversity. Two large prophylactic trials in high incidence, clade C epidemic regions in southern Africa are imminent; passive administration of the monoclonal antibody VRC01, and active immunization with a clade C modified RV144-like vaccines. We have created a large representative panel of C clade viruses to enable assessment of antibody responses to vaccines and natural infection in Southern Africa, and we investigated the genotypic and neutralization properties of recently transmitted clade C viruses to determine how viral diversity impacted antibody recognition. We further explore the implications of these findings for the potential effectiveness of these trials. A panel of 200 HIV-1 Envelope pseudoviruses was constructed from clade C viruses collected within the first 100 days following infection. Viruses collected pre-seroconversion were significantly more resistant to serum neutralization compared to post-seroconversion viruses (p = 0.001). Over 13 years of the study as the epidemic matured, HIV-1 diversified (p = 0.0009) and became more neutralization resistant to monoclonal antibodies VRC01, PG9 and 4E10. When tested at therapeutic levels (10ug/ml), VRC01 only neutralized 80% of viruses in the panel, although it did exhibit potent neutralization activity against sensitive viruses (IC50 titres of 0.42 μg/ml). The Gp120 amino acid similarity between the clade C panel and candidate C-clade vaccine protein boosts (Ce1086 and TV1) was 77%, which is 8% more distant than between CRF01_AE viruses and the RV144 CRF01_AE immunogen. Furthermore, two vaccine signature sites, K169 in V2 and I307 in V3, associated with reduced infection risk in RV144, occurred less frequently in clade C panel viruses than in CRF01_AE viruses from Thailand. Increased resistance of pre-seroconversion viruses and evidence of antigenic drift highlights the value of using panels of very recently transmitted viruses and suggests that interventions may need to be modified over time to track the changing epidemic. Furthermore, high divergence such as that observed in the older clade C epidemic in southern Africa may impact vaccine efficacy, although the correlates of infection risk are yet to be defined in the clade C setting. Findings from this study of acute/early clade C viruses will aid vaccine development, and enable identification of new broad and potent antibodies to combat the HIV-1 C-clade epidemic in southern Africa.
The development of effective biomedical intervention strategies to prevent HIV-1 infection remains a global priority. To support these efforts, two large immunization trials in high incidence, clade C epidemic regions in southern Africa are imminent. The first, a Phase 3 efficacy trial using a vaccine similar to the one used in the RV144 trial modified to include clade C antigens will be tested to determine if the protection observed in the RV144 vaccine trial in Thailand can be replicated in this high incidence setting (http://vaccineenterprise.org/content/P5Partnership). The second is a Phase 2b trial to evaluate if passive administration of the VRC01 monoclonal antibody, that targets the viral CD4 binding site (CD4bs), reduces HIV-1 acquisition . Both interventions rely on the induction of HIV-specific antibodies against the HIV-1 envelope glycoprotein. HIV-1 is extraordinarily diverse, and evaluation of potential coverage by these intervention strategies would therefore need to take envelope diversity into account. As there is a severe HIV-1 transmission bottleneck that may affect viral phenotype [2–7], studies that aim to elucidate the target for active and passive immunization should ideally be done on viruses that are collected soon after transmission.
The extraordinary diversity of HIV-1 is a barrier to achieving protection in active and passive immunization studies. Several large prophylactic trials in clade C epidemic regions of Africa that rely on antibody-mediated protection are imminent, including passive immunization with the broadly neutralizing antibody (bnAb) VRC01, and a vaccine efficacy study of the RV144 regimen tailored for clade C. Using a large panel of 200 clade C pseudotyped viruses from acute/early infection, we observed that pre-seroconversion viruses were more resistant to antibody neutralization compared to post-seroconversion viruses. Additionally, we provide evidence of antigenic drift in certain bnAb targets including VRC01, which we estimated will only block ~80% of clade C viruses at its most efficacious dose. Furthermore, the higher divergence of clade C viruses from candidate clade C vaccines, compared to CRF01_AE viruses to the clade matched vaccine used in the RV144 vaccine, may make protection harder to achieve in clade C epidemic regions. Our study therefore provides a comprehensive analysis of viral traits that affect antibody recognition and interrogates how planned clinical trials may perform in the clade C epidemic of southern Africa.