The HIV Research for Prevention (HIVR4P) 2018 conference is underway in Madrid, Spain. HIVR4P is the world’s largest scientific meeting dedicated to HIV biomedical research.
Below are some highlights from VIDD faculty presenting at the conference.
DNA vaccines hold great promise for HIV prevention research
OCTOBER 24, 2018 – Scientific presentations by the HIV Vaccine Trials Network (HVTN) at the HIVR4P conference showed promising early-stage clinical findings that advance the development of DNA vaccines to prevent HIV infection.
While traditional viral vector vaccines involve weakened or killed forms of whole pathogens or specific protein components that generate antibody and T-cell responses, DNA vaccines aim to deliver a small circular piece of DNA containing genes encoding pathogen antigens directly to cells. The body’s cells use this DNA to produce the antigens that trigger immune responses. Thus far, no DNA vaccines have been approved for human use in the United States. Two presentations at HIVR4P indicated that candidate HIV DNA vaccines can elicit strong anti-HIV immune responses in clinical trial participants.
DNA and protein HIV vaccine regimen elicited stronger antibody and cellular immune responses than a canarypox and protein HIV vaccine regimen.
DNA vaccines are relatively easy and inexpensive to manufacture but do not always produce strong immune responses. HVTN scientists reported that an experimental HIV DNA and protein vaccine regimen assessed in the HVTN 111 clinical trial elicited stronger immune responses in study participants than a regimen based on canarypox and protein vaccines evaluated in the HVTN 100 clinical trial.
The HVTN 111 regimen included groups who received two initial, or “prime,” doses of a DNA vaccine given either by needle and syringe or by a needle-free injector called a Biojector, followed by two booster doses of the DNA vaccine plus an HIV protein containing an adjuvant to enhance immune responses (see figure). HVTN 100 tested a regimen comprising two doses of a canarypox-vectored vaccine called ALVAC, followed by two doses of ALVAC plus the same adjuvanted protein used in HVTN 111. These results suggest that DNA vaccines should be considered for future HIV vaccine strategies. The findings were reported at an HIVR4P oral presentation titled DNA-prime Induces Higher Magnitude Humoral Responses than ALVAC-prime in HIV Vaccine Regimens with the Same Protein Boost.
"Our results suggest that HIV vaccine strategies should prioritize DNA priming with an adjuvanted protein boost if the quality and durability of antibody and cellular responses also indicate superiority over ALVAC priming,” said Zoe Moodie, Ph.D., faculty statistician in VIDD. “Further evaluation is needed to determine whether the delivery of DNA by Biojector elicits stronger cellular immune responses that warrant its use over the traditional needle and syringe,” she concluded.
Image by Lisa Donohue
Vaccine delivery by electroporation through the skin requires one-fifth of the dose needed for an intramuscular vaccine for an equivalent immune response.
OCTOBER 24, 2018 – Researchers are pursuing strategies to make DNA vaccines more effective in humans. One new approach is detailed in the abstract Immune Responses to PENNVAX-GP® HIV DNA Vaccine plus IL-12 are Equivalent or Superior when Delivered by Intradermal vs. Intramuscular Electroporation, presented today at an oral scientific session. In this phase 1 HVTN 098 clinical trial, DNA vaccines were delivered via patients’ skin or muscle with an electroporation device, which makes cell membranes more permeable to DNA with a pulse of electricity.
The electroporation device was used to encourage cells to take up the DNA vaccine, called PENNVAX-GP. The vaccine was delivered along with IL-12 (interleukin 12), which can stimulate the function of T cells, a key component of the immune response. The study authors found that with the use of electroporation and IL-12, higher magnitude immune responses to the DNA vaccine were seen, and that delivery through the skin required only one-fifth of the dose needed for a vaccine delivered to the muscle to achieve the same immune response.
Dr. J. Joseph Kim, Inovio’s President & CEO, said, “Inovio and the HVTN share a goal to develop a successful HIV vaccine as soon as possible. We are grateful for their partnership in that effort. At Inovio, we are truly pleased to see these robust immune response data and they are remarkably consistent with our other vaccine data reported from our Ebola, Zika and MERS clinical trials in terms of demonstrating very favorable vaccine response rates with a good safety profile. We look forward to further advancing PENNVAX-GP into later-stage clinical development with our partners and collaborators.”
Much remains to be accomplished in the field of DNA vaccines, but HVTN researchers are making bold strides in their pursuit to find a safe and effective HIV vaccine.
 The potent immunogenicity and dose-sparing effect of intradermal delivery of DNA delivered via electroporation (boosted with MVA) was published in 2008. The Journal of Infectious Diseases, Volume 198, Issue 10, 15 November 2008, Pages 1482–1490, https://doi.org/10.1086/592507
Gut microbiome may impact HIV vaccine immune responses
OCTOBER 23, 2018 – Preliminary evidence presented at the HIV Research for Prevention (R4P) Conference in Madrid, Spain suggests that the composition of the human gut microbiome may inform how well an experimental HIV vaccine can elicit an immune response. Vaccines reduce the risk of an infection by helping the human immune system to fight disease without exposing it to disease symptoms.
In a late breaker abstract presentation titled: Human gut microbiota are associated with HIV-reactive immunoglobulin at baseline and following HIV vaccination, James Kublin, M.D. of the HIV Vaccine Trials Network (HVTN) explained that the human microbiome and immune system shape each other through lifelong interactions. He and his team used 16S ribosomal RNA sequencing of stool samples to understand the role of the human gut microbiome in modulating the immune response to two experimental HIV vaccines.
The microbiota composition of study participants, from the HVTN 096 clinical trial, was analyzed at baseline and then at two weeks and at six months post vaccination. HVTN 096 was a phase 1, double blind, placebo-controlled clinical trial to evaluate the safety and to compare the priming ability of NYVAC alone versus NYVAC + AIDSVAX® B/E, and DNA alone versus DNA + AIDSVAX® B/E when followed by NYVAC + AIDSVAX® B/E boosts in healthy, HIV-1-uninfected adult participants.
Detection of antibodies directed against the envelope (Env) glycoprotein 41 (gp41) were generally much higher than baseline responses to other HIV Env antigens, which is consistent with there being cross-reactivity between responses to gp41 and other immunogens, potentially from commensal organisms such as E. coli. One microbial consortium that associated with high gp41 responses at baseline also associated with lower vaccine-induced gp120 responses at primary and durability timepoints (two weeks and six months post vaccination, respectively) and lower V1V2 responses at the durability timepoint. Conversely, a second consortium of microbes associated with low baseline gp41 responses and higher gp120 responses at primary and durability timepoints, including the V1V2 responses 6 months after the last vaccination.
“We have further evidence that the microbiome is likely impacting vaccine responses, and that these responses may play a role in whether people are protected from HIV or not,” said James Kublin, executive director of the HVTN and principal staff scientist of VIDD.
Serum-neutralizing antibody titers correlate strongly with protection against SHIV infection
OCTOBER 24, 2018 – Results from a meta-analysis combining information from a variety of nonhuman primate SHIV (simian/human immunodeficiency virus) challenge studies suggest that the concentration of neutralizing HIV antibodies in the bloodstream correlates strongly to protection against SHIV infection. The data analyzed originated from 12 published and 5 unpublished SHIV challenge studies spanning 2010–2017, which focused on seven SHIV strains and 16 broadly neutralizing monoclonal antibodies (bnAbs) targeting five envelope epitope regions. In each challenge study, primates were infused with a single bnAb to neutralize SHIV.
Researchers used data from the previous SHIV studies to estimate the dilution level of antibody at which 50% of SHIV would be neutralized, i.e., the serum 50 percent neutralization titer or inhibitory dilution (ID50). Across all experimental factors, including epitope category, challenge virus, dose and sex, administering a serum-neutralizing ID50 titer strongly correlated with protection against SHIV infection. For every ten-fold increase in ID50 titer, the study authors found around 95 percent reduction in the odds of SHIV infection, suggesting that the measurement of serum neutralizing titers is a key factor in bnAb clinical efficacy trials and in evaluation of vaccines designed to elicit neutralizing antibodies.
“Characterizing the relationship between neutralizing antibody titers and the level of protection in nonhuman primate challenge studies will be helpful in understanding and predicting the efficacy of bnAbs in human trials. Our analyses suggest that serum-neutralizing antibody titers are strong correlates of protection against SHIV infection,” said Ying Huang, Ph.D., associate member in VIDD.
The study was a collaboration between Fred Hutchinson Cancer Research Center, the Vaccine Research Center of the NIH and the Scripps Center for HIV/AIDS Immunology and Immunogen Discovery (CHAVI-ID). “The neutralizing antibody titers that Ying has determined are also important to give us an estimate of what we are shooting for from an HIV vaccine,” commented Dennis Burton, director of CHAVI-ID.
Importance of the meta-analysis results to the Antibody Mediated Prevention (AMP) studies
VRC01, an antibody initially identified in an individual infected with HIV for over 10 years but who had never developed AIDS, has been shown to block over 90 percent of tested HIV strains, and was advanced to trials in humans. The AMP studies, which commenced in 2016, aim to assess VRC01’s ability to prevent HIV by comparing HIV infection rates in 4,600 volunteers at high risk of acquiring HIV infection, who receive varying amounts of VRC01 or a placebo. The meta-analysis results reaffirm the importance of analyzing the measurement of serum-neutralizing titers against HIV.
Though much remains to be accomplished in the field of HIV vaccine research, HVTN researchers are making bold strides in their pursuit to find a safe and effective HIV vaccine.
Access HVTN conference program: http://www.hvtn.org/en/media-room/hvtn-hivr4p-scheduleofevents.html