Induction of circulating T follicular helper cells and regulatory T cells correlating with HIV-1 gp120 variable loop antibodies by a subtype C prophylactic vaccine tested in a Phase I trial in India

Abstract

A Phase I HIV-1 vaccine trial sponsored by the International AIDS Vaccine Initiative (IAVI) was conducted in India in 2009 to test a subtype C prophylactic vaccine in a prime-boost regimen comprising of a DNA prime (ADVAX) and MVA (TBC-M4) boost. The trial demonstrated that the regimen was safe and well tolerated and resulted in enhancement of HIV-specific immune responses. Preliminary observations on vaccine-induced immune responses were limited to analysis of neutralizing antibodies and IFN-γ ELISPOT response. The present study involves a more detailed analysis of the nature of the vaccine-induced humoral immune response using specimens that were archived from the volunteers at the time of the trial. Interestingly, we found vaccine induced production of V1/V2 and V3 region-specific antibodies in a significant proportion of vaccinees. Variable region antibody levels correlated directly with the frequency of circulating T follicular helper cells (Tfh) and regulatory T cells (Treg). Our findings provide encouraging evidence to demonstrate the immunogenicity of the tested vaccine. Better insights into vaccine-induced immune responses can aid in informing future design of a successfulHIV-1 vaccine.

T follicular helper cell heterogeneity: Time, space, and function

“…Since then, subsets of CD4 + T cells with "Tfhlike" characteristics, frequently referred to as circulating Tfh (cTfh) [114][115][116] Patients with autoimmunity such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome have increased frequency of cTfh cells with an "activated" phenotype which correlates with disease activity. Since then, subsets of CD4 + T cells with "Tfhlike" characteristics, frequently referred to as circulating Tfh (cTfh) [114][115][116] Patients with autoimmunity such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome have increased frequency of cTfh cells with an "activated" phenotype which correlates with disease activity.…”

“…112,113 Induction of cTfh cells has also been observed in volunteers receiving in-trial HIV vaccines and a novel Escherichia coli vaccine. [114][115][116] Patients with autoimmunity such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome have increased frequency of cTfh cells with an "activated" phenotype which correlates with disease activity. [117][118][119][120][121] In HIV-infected individuals, the frequency of CXCR3-cTfh cells correlate with the generation of broadly neutralizing antibody.…”

Induction and maintenance of bi-functional (IFN-γ + IL-2+ and IL-2+ TNF-α+) T cell responses by DNA prime MVA boosted subtype C prophylactic vaccine tested in a Phase I trial in India

“…We first evaluated vaccine-induced IFN-γ production using the ELISpot assay and found that vaccination induced significantly higher IFN-γ responses, particularly in response to Env and Gag antigens, clearly indicating that vaccination resulted in successful priming of the immune system. Subsequently we published another report describing in detail the humoral immune responses induced by this vaccine [43]. The magnitude of the IFN-γ response was found to be higher in volunteers who received the heterologous regimen, as compared to those who received the homologous regimen.…”

“…Although cell mediated immune responses were not preferentially expanded in Group B participants, we reported in an earlier study that vaccination resulted in a strong induction of antibodies targeting the variable regions of HIV-1gp120, which correlated positively with induction of long-lasting plasma B cells and T Follicular Helper cells in volunteers who received only MVA [43]. Interesting observations of HIV-specific antibodies targeting the rgp41 Env, rgp140 Env, p24 Gag, and rgp120 Env were also made in the P002 trial conducted at UK with the same vaccine constructs [26].…”

Evaluation of antiviral T cell responses and TSCM cells in volunteers enrolled in a phase I HIV-1 subtype C prophylactic vaccine trial in India

“…Previously, we examined vaccine-induced humoral and cell-mediated responses to the same subtype C HIV-1 vaccine (ADVAX DNA prime and MVA boost) tested in a phase I clinical trial in India (P001 trial) and reported encouraging findings [30,31]. In the current study, we investigated vaccine-induced peripheral T SCM cells and in vitro viral inhibitory capacity of vaccine-induced CD8 + T cells in the same cohort.…”