Vaccine and Infectious Disease Division

A look at the innate immune response to HIV vaccines with Erica Andersen-Nissen

Jennifer Andersen-Nissen

VIDD postdoctoral fellow Dr. Erica Andersen-Nissen came to the Center in 2006, after a PhD at the University of Washington and the Institute for Systems Biology. Before her doctoral work, Andersen-Nissen studied in Tanzania and taught in Botswana, where she became interested in research with a potential direct clinical impact on HIV.

An effective vaccine must be able to spur robust and specific immune responses in recipients.  However, very little is known about the molecular changes that happen immediately after vaccination in humans – most vaccine research has focused on later changes in the immune system, known as the adaptive immune response.  Now, VIDD postdoctoral fellow Dr. Erica Andersen-Nissen is working to define early molecular and cellular changes, also known as the innate immune response, that occur after vaccination with candidate HIV vaccines.

“Nobody’s really taken a comprehensive approach, with the idea that once you learn something about the innate immune response, then you could correlate it with ensuing adaptive responses,” she said.

The human immune system has multiple waves of defense, varying in speed and specificity.  The innate immune system responds immediately to a foreign invader, both attacking and sensing the class of pathogen.  This early response then triggers the adaptive immune system, which mounts a targeted defense against the specific pathogen.  While a successful vaccine must trigger a specific adaptive immune response, so that the body retains a lasting memory of the disease, researchers think how a vaccine triggers the innate immune response is also important.

To learn about the body’s early immune responses to vaccines, Andersen-Nissen, who is a fellow in VIDD co-director Dr. Julie McElrath’s lab, is looking at changes immediately following vaccination with candidate HIV vaccines from HVTN trials.  Specifically, she and her colleagues take samples of whole blood and peripheral blood mononuclear cells (PBMC, a purified subset of blood cells) before and during the first few days following vaccination, and assay cellular and molecular changes in these samples.

“We went into it not knowing whether intramuscular vaccination would produce noticeable changes in the blood,” Andersen-Nissen said.  “We were fortunate to find big responses.”

Andersen-Nissen is looking at innate immune responses to several candidate HIV vaccines currently under development in the HVTN.  Her first approach was through the HVTN 071 trial, which assayed the early immune responses to the Merck HIV vaccine candidate used in the Step study.   Both the Step study and HVTN 071 were halted early when it was shown that the candidate vaccine did not protect against HIV, but the researchers were still able to collect extensive samples from 11 participants in HVTN 071.  Even though the Merck vaccine was not effective against HIV, there are still insights to be gained, Andersen-Nissen said.

“The goal is to develop profiles of different classes of vaccines and adjuvants, based on the innate immune responses they trigger,” she said.  “Then comparing those with licensed vaccines that actually work is vitally important – the ultimate goal being to correlate certain innate immune responses with adaptive immune responses of successful vaccines.”

To examine innate immune responses to the Merck vaccine, Andersen-Nissen and colleagues collected samples before vaccination and four to six hours, 24 hours, three days, and one week after vaccination.  They first looked at the types of cells present in the blood, and found that both T cells and B cells rapidly exited the bloodstream within 24 hours after vaccination, while levels of certain other immune cells – monocytes and dendritic cells – increased in the circulation in the first few days following vaccination.  The researchers found changes in protein levels and gene expression in the blood that signal a “typical” inflammatory response.   Compared to before vaccination, they found that 2,000 different genes were turned on or off in PBMC at 24 hours after vaccination.

To compare the effects of different vaccines on the innate immune system, Andersen-Nissen and colleagues looked at the overlap between their data on early gene expression changes induced by the Merck HIV vaccine and data from other researchers on changes induced by the licensed and effective yellow fever vaccine.  While gene expression changes occurred more rapidly in response to the HIV vaccine, many genes with increased expression were identical in both data sets.  Genes with decreased expression were quite different between the studies.  This may mean that there is a “core” of antiviral genes turned on by the innate immune system in response to any viral-vectored vaccine, Andersen-Nissen said.

The findings from HVTN 071 indicate that the majority of changes in the innate immune system happen in the first 24 hours following vaccination.  To delve deeper into this rapid immune response and to figure out which innate responses correlate with adaptive immune responses, Andersen-Nissen and VIDD postdoctoral fellow Dr. Antje Heit are working on a new study, HVTN 089, to collect hourly samples in the first day after vaccination.  Andersen-Nissen is also looking at the innate immune response to other candidate HIV vaccines tested in the HVTN, and is expanding sampling to sites outside of Seattle.  Ultimately, correlating certain early immune responses with the likelihood of vaccine success will give much earlier reads in clinical trials of candidate HIV vaccines, as well as enabling the design of new adjuvants and vaccine vectors to hopefully elicit better protection against HIV.