The phase II STEP vaccine trial was stopped after an interim analysis showed no efficacy in preventing HIV infection in at-risk individuals. It was noted that a subset of participants who had previous immunity in the form of neutralizing antibodies to the adenovirus 5 (Ad5) vector used to deliver the vaccine actually showed a trend toward an increased rate of HIV infection. Finding an explanation for this increased susceptibility to infection remains a major focus for HIV vaccine researchers.
These individuals were found to have high blood Ad5 neutralizing antibody (nAb) titers, the main immune gatekeeper in most vaccine strategies. Antibodies produced in response to previous infection neutralize viruses by binding to them and preventing their entry into host cells. They work in concert with other immune cells, including CD4 T-cells, which build a memory bank against future infection. In HIV infection, the virus attaches specifically to CD4 receptors on activated CD4 T-cells, establishing a stronghold and replicating.
Of the STEP findings, many researchers hypothesize that the T-cells of individuals in this high-Ad5-antibody group were activated by the Ad5-vaccine vector, creating more activated CD4 T-cells which then served as targets for the HIV virus to establish an infection.
“Our findings disprove the favored hypothesis,” says co-lead author Hildegund C.J. Ertl, M.D., director of The Wistar Institute Vaccine Center. “There was nothing to indicate that pre-existing neutralizing antibodies correlated with numbers of activated CD4 T-cells to Ad5, which could have provided additional targets for HIV infection following subsequent exposure.”
Seeking to understand the relationship between previous neutralizing antibodies to Ad5 and Ad5-specific T-cell responses, the team, headed by Michael R. Betts, Ph.D., of the University of Pennsylvania School of Medicine Department of Microbiology, Center for AIDS Research, and Wistar Institute Vaccine Center, analyzed blood samples from 40 healthy participants in the phase I safety trial of the STEP HIV vaccine for immune response to Ad5 particles. The blood samples, which came from individuals with both high and low nAb titers and thus varying degrees of pre-existing neutralizing antibodies to Ad5, had been taken from participants at baseline, before administration of the Ad5 vector vaccine under study. From their current Ad5 assay, the team found no correlation between nAb titers at baseline and CD4 T-cell frequency.
“Ad-specific CD4 T-cells are exceptionally common in humans, regardless of the level of neutralizing antibodies to Ad5,” says Betts. “This is probably the major factor that disproves the main hypothesis proposed to explain the STEP trial results.”
The team next questioned whether the Ad5-specific CD4 T-cells functioned any differently before or after administering the Ad5 vector. They found no significant difference in activation or expansion of CD4 T-cells in either the high- or the low-Ad5 antibody groups.
“It doesn’t appear that vaccination increases the pool of potentially infectable CD4 T-cells in people with pre-existing immunity to Ad5,” Ertl says. “When you look at the data together, they suggest we must look elsewhere to explain the link between previous Ad5 immunity and increased acquisition of HIV infection.”
Study investigators include Natalie A. Hutnick, B.S., and Diane G. Carnathan, M.S., University of Pennsylvania School of Medicine Department of Microbiology and Center for AIDS Research; Sheri A. Dubey, Kara S. Cox, Lisa Kierstead, Michael N. Robertson, M.D., and Danilo R. Casimiro, Ph.D., of Merck Research Laboratories; and Sarah J. Ratcliffe, Ph.D., of the University of Pennsylvania School of Medicine Department of Biostatistics and Epidemiology.
The study was supported by a collaborative grant from the National Institutes of Health to Ertl and Betts.
The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has long held the prestigious Cancer Center designation from the National Cancer Institute. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. The Wistar Institute: Today’s Discoveries – Tomorrow’s Cures. On the Web at www.wistar.org.
Susan I. Finkelstein | Newswise Science News
New discoveries predict ability to forecast dementia from single molecule
12.12.2018 | UT Southwestern Medical Center
Pain: Perception and motor impulses arise in the brain independently of one another
12.12.2018 | Technische Universität München
What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...
A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.
The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...
A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.
Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...
Over the last decade, there has been much excitement about the discovery, recognised by the Nobel Prize in Physics only two years ago, that there are two types...
What if a sensor sensing a thing could be part of the thing itself? Rice University engineers believe they have a two-dimensional solution to do just that.
Rice engineers led by materials scientists Pulickel Ajayan and Jun Lou have developed a method to make atom-flat sensors that seamlessly integrate with devices...
12.12.2018 | Event News
10.12.2018 | Event News
06.12.2018 | Event News
13.12.2018 | Life Sciences
13.12.2018 | Physics and Astronomy
13.12.2018 | Earth Sciences