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Sunday, April 14, 2024

UC Davis study on rectal microbes sparks hope for more effective HIV vaccine

Researchers looked at interaction of gut microbiome, HIV vaccine in rhesus macaques

UC Davis researchers are investigating the gut and vaginal microbes of the primate species rhesus macaques for clues to developing a more effective vaccine for human immunodeficiency virus, or HIV.

In a study published last December in the open-access journal mSphere, a team of scientists directed by Dr. Smita Iyer — an assistant professor of pathology, microbiology, and immunology — explored how an experimental vaccine resembling the HVTN 111 vaccine impacted the microbiome environments of rhesus macaques and vice versa. HVTN 111 is currently wrapped up in human clinical trials, so this DNA vaccine was of particular interest to the researchers.

“As an immunologist I am driven to understanding how host factors modulate vaccine immunogenicity so we can use this information to develop vaccines against challenging infectious diseases,” Iyer wrote via email.

The findings of Iyer’s team, which included scientists from Emory University and the University of Pittsburgh, are the first to directly suggest that the immune actions of an HIV vaccine are influenced by bacteria inside our bodies.

“One of the bigger questions that has eluded the field or that people haven’t addressed substantially yet is how immunizations can affect the microbiome,” said Sonny Elizaldi, a second-year graduate student studying immunology at UC Davis and the lead author on this research study. “We wanted to ask how the vaccine affects both the fecal and vaginal microbiomes.”

The team’s research cites the rectum and vagina as the two main sites where HIV is generally transmitted between humans. Before the experimental HIV vaccine was administered, DNA samples from these two compartments were first sequenced to establish an understanding of initial microbiome compositions in each macaque’s rectum and vagina. 

Data from the study showing differences in the microbiome composition of the rectum and the vagina established that the compartments were independent of one another. This is important because it allowed the research team to investigate the rectum and the vagina as separate compartments, Elizaldi said.

A series of three vaccines — the first two containing viral HIV DNA and the third containing viral HIV protein — was administered eight weeks apart to both sites in the rhesus macaques. The immune responses at each site were characterized at zero, one and four weeks after the third immunization by data quantifying CD4 T cells, immunoglobulin A and G (IgA and IgG) antibodies and glycoprotein gp120 and gp140 antibodies. High concentrations of each indicate greater immune responses.

Although the levels of Lactobacillus and Clostridium — two prevalent gut bacteria  — in the rectum were unaffected by the HIV vaccine, the relative levels of bacteria between macaques were found to positively correlate with the recorded immune response in that animal. Conversely, levels of Prevotella, another type of gut bacteria, decreased with greater immune responses. Overall, several types of bacteria in the rectum saw significant changes after immunization.

“[Lactobacillus and Clostridium] bacteria could possibly be targeted to induce stronger antibody responses, so maybe supplementation with certain types of bacteria before you get immunized could, in fact, maybe help produce stronger antibody responses,” Elizaldi said.

When similar data was obtained from macaques that had only received a measles booster prior to experimentation, these differences were not observed, indicating that the response to the HIV vaccine seen in the rectal microbiome of the experimental group was likely due to vaccination, according to Elizaldi.

The composition of the vaginal microbiome was relatively unaltered by vaccination, suggesting that “the vaginal microbiome is maybe just a lot more resilient to change in the context of an immunization platform,” Elizaldi said. 

It is also possible that microbes in the vagina respond quickly to an initial or second immunization, but not to a third immunization, according to Elizaldi. This could explain why, when microbial composition was examined 16 weeks after the first of three vaccines was initially administered, the vaginal microbiome seemed unchanged.

The microbiome composition was tracked up until four weeks after the third immunization, so a third possibility is that vaginal microbes are slower to respond to vaccination than rectal microbes.

One limitation to developing effective HIV vaccines is that the immune response to the vaccine is often short-lived.

“One of the problems within the HIV vaccine field is developing long-lived antibodies,” Elizaldi said. “That’s something that is really eluding the field, and, I mean, that’s really the golden ticket there. If you could induce long-lived antibodies with an HIV vaccine, you’d be a little bit closer to establishing a successful vaccine, so that’s what everybody in the field is really gunning for now.”

Although this study evaluated the vaccine’s microbiome interactions specifically in macaques, the conclusions of this study could eventually be generalized to human models.

“Rhesus macaques for a long time have been a really solid model for HIV,” Elizaldi said. “That’s primarily [because] the infection kinetics, the kinetics of viral entry into the host and replication within the rhesus macaques, mimic very closely the human infection.”

How bacteria enhance or hinder the immune system’s response to a vaccine is not fully understood. But scientists’ knowledge of microbe-vaccine interactions can be refined with future investigations targeting specific genera of bacteria. Such studies could herald the arrival of an improved HIV vaccine for humans, reshaping how we treat autoimmune immunodeficiency syndrome, a disease caused by HIV, and providing hope for the millions of people who have it.

“This [research] opens the door into understanding how we can possibly target immunizations to be more synergistic with the microbiome,” Elizaldi said. 

Iyer, Elizaldi and their colleagues drew on the help of multiple departments and microbiome experts to complete this study. A team of bioinformaticians from the Bioinformatics Core Facility at the UC Davis Genome Center contributed to data analysis. 

“The most challenging aspect of the study was synthesizing complex and large data sets to understand biology,” Iyer said. 

The team also included Dr. Reben Raeman, an assistant professor of pathology at the University of Pittsburgh, who “provided consultation to the Iyer lab on experimental design and data interpretation,” according to Raeman.

The macaques in this study were part of an adult female cohort at the California National Primate Research Center, a research unit of UC Davis. All animals tested negative for simian immunodeficiency virus, a common analog of HIV in primates.

Written by: Daniel Erenstein — science@theaggie.org


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