Functional profile to HIV vaccine elicited antibodies in infants

HIV 疫苗的功能特征在婴儿中引发抗体

• 批准号: 9882942
• 负责人: Genevieve Giny Fouda Amou ou
• 金额: $ 40.11万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9882942
• 关键词: Address; Adjuvant; Adult; Affinity; Antibodies; Antibody Response; Antigens; Antiviral Agents; B-Lymphocytes; Cells; Characteristics; Childhood; Communicable Diseases; Complement Activation; Data; Databases; Development; Evolution; Fc Receptor; Future; Genes; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; HIV-1 vaccine; Human; Human Milk; Immune; Immune response; Immune system; Immunization; Immunize; Immunogenetics; Immunoglobulin G; Infant; Infection; Institutes; Intervention; Length; MF59; Macaca mulatta; Mediating; Memory B-Lymphocyte; Monoclonal Antibodies; Mother-to-child HIV transmission; Mutation; Pathway interactions; Phagocytosis; Plasma; Population; Pregnant Women; Reporting; Risk; Specificity; Technology; Testing; Time; Up-Regulation; Vaccinated; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Viral; Viral Antibodies; aluminum sulfate; antibody-dependent cell cytotoxicity; antiretroviral therapy; base; design; efficacy testing; genetic signature; glycosylation; insight; pathogen; pediatric human immunodeficiency virus; prevent; receptor binding; recruit; response; screening; sexual debut; transcriptome; transcriptome sequencing; transmission process; vaccine candidate; vaccine efficacy; vaccine response; vaccine trial; whole genome

Eliminating breast milk HIV-1 transmission will likely require a combination of approaches, including immune- based interventions such as a pediatric HIV-1 vaccine. Only a few vaccine trials have included pediatric populations and none of them tested efficacy. Because of differences between the adult and infant immune system, it is unclear if antibodies elicited by HIV vaccination in adults and infants are able to mediate similar effector functions. This study will address this gap by comparing the functional profile of antibodies elicited by the same adjuvanted HIV vaccines in adults and infants. Insights on vaccine protection can be drawn from the moderately effective adult RV144 trial in which a reduced risk of HIV-1 acquisition was associated with high levels of IgG against the HIV-1 Envelope (Env) V1V2 loops. We have demonstrated that infant vaccination with a rgp120/MF59 vaccine induces plasma levels of potentially-protective anti-V1V2 IgG that are 22 times higher than levels found in adult RV144 vaccinees. Importantly, it was recently reported that MF59 does not induce high magnitude potentially-protective antibody responses in adults. Yet, our preliminary data show that infants immunized with the rgp120/MF59 vaccine developed higher magnitude HIV Env-specific responses than adults immunized with the same vaccine. This suggests that distinct adjuvants may differently modulate vaccine- elicited responses in adults and infants. These differences are likely to influence effector functions and dictate vaccine efficacy. The objective of this application is to evaluate the function of infant vaccine-elicited Env- specific antibodies and define the impact of different adjuvants on infant functional antibody responses. Our central hypothesis is that antibodies elicited by infant HIV-1 vaccination are capable of mediating distinct anti- viral effector functions when compared to adult antibodies, and infant antibody functional profile is influenced by the vaccine adjuvant. Our central hypothesis will be tested in the following specific aims: 1) Define the functional profile of HIV vaccine-elicited antibodies in infants in comparison with that of adults immunized with the same HIV Env vaccine; 2) Define the evolution, specificity, and function of mAbs isolated from Env-specific memory B cells of HIV-exposed HIV-vaccinated infants; and 3) Assess the impact of vaccine adjuvants on HIV vaccine antibody Fc-mediated functions in infant rhesus macaques (RMs) and the relationship between specific B cell gene pathways upregulation and effector function. We expect that this study will identify differences in effector functions between adults and infants, highlighting the need to test promising vaccine candidates in pediatric populations. In addition, the identification of gene pathways associated with optimal vaccine responses through our proposed ‘omics approach, will allow for the rational design and screening of infant vaccine and adjuvant candidates for their ability to target these B cell gene signatures.

Eliminating breast milk HIV-1 transmission will likely require a combination of approaches, including immune- based interventions such as a pediatric HIV-1 vaccine. Only a few vaccine trials have included pediatric populations and none of them tested efficacy. Because of differences between the adult and infant immune system, it is unclear if antibodies elicited by HIV vaccination in adults and infants are able to mediate similar effector functions. This study will address this gap by comparing the functional profile of antibodies elicited by the same adjuvanted HIV vaccines in adults and infants. Insights on vaccine protection can be drawn from the moderately effective adult RV144 trial in which a reduced risk of HIV-1 acquisition was associated with high levels of IgG against the HIV-1 Envelope (Env) V1V2 loops. We have demonstrated that infant vaccination with a rgp120/MF59 vaccine induces plasma levels of potentially-protective anti-V1V2 IgG that are 22 times higher than levels found in adult RV144 vaccinees. Importantly, it was recently reported that MF59 does not induce high magnitude potentially-protective antibody responses in adults. Yet, our preliminary data show that infants immunized with the rgp120/MF59 vaccine developed higher magnitude HIV Env-specific responses than adults immunized with the same vaccine. This suggests that distinct adjuvants may differently modulate vaccine- elicited responses in adults and infants. These differences are likely to influence effector functions and dictate vaccine efficacy. The objective of this application is to evaluate the function of infant vaccine-elicited Env- specific antibodies and define the impact of different adjuvants on infant functional antibody responses. Our central hypothesis is that antibodies elicited by infant HIV-1 vaccination are capable of mediating distinct anti- viral effector functions when compared to adult antibodies, and infant antibody functional profile is influenced by the vaccine adjuvant. Our central hypothesis will be tested in the following specific aims: 1) Define the functional profile of HIV vaccine-elicited antibodies in infants in comparison with that of adults immunized with the same HIV Env vaccine; 2) Define the evolution, specificity, and function of mAbs isolated from Env-specific memory B cells of HIV-exposed HIV-vaccinated infants; and 3) Assess the impact of vaccine adjuvants on HIV vaccine antibody Fc-mediated functions in infant rhesus macaques (RMs) and the relationship between specific B cell gene pathways upregulation and effector function. We expect that this study will identify differences in effector functions between adults and infants, highlighting the need to test promising vaccine candidates in pediatric populations. In addition, the identification of gene pathways associated with optimal vaccine responses through our proposed ‘omics approach, will allow for the rational design and screening of infant vaccine and adjuvant candidates for their ability to target these B cell gene signatures.