Two months after investigators halted a once-promising HIV vaccine trial, a horde of mice is delivering more bad news. The viral packaging used in another HIV vaccine has hurt, not helped, the animals’ immune systems.
The finding prompted study leader Hildegund C.J. Ertl of the Wistar Institute in Philadelphia to call for a pause in human tests of the vaccine that delivers snippets of HIV to people via a genetically altered adeno-associated virus (AAV). This viral package is designed to train the immune system to recognize and attack HIV. But vaccines employing AAV “may potentially cause harm,” Ertl says. “Without additional preclinical studies, they should not be used in humans.”
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In a clinical trial in Africa, 91 volunteers have received the AAV vaccine, which was developed by the International AIDS Vaccine Initiative (IAVI). The organization says that even before the new mouse study, it had decided not to conduct further human trials of the vaccine because of “relatively modest immune responses” in the volunteers.
In Ertl’s study, mice receiving the AAV vaccine showed signs of immune system impairment. Ideally, vaccines induce a population of immune T cells that “remember” what a particular infectious organism looks like. The next time the T cells encounter the same organism, the cells activate, proliferate, and attack the infection.
But T cells in Ertl’s mice appeared exhausted. They generated few important immune-activating chemicals called cytokines. More important, these cells failed to proliferate when exposed to the snippet of HIV they were supposed to recognize. Ertl concludes that the vaccine’s AAV overstimulated and depleted the animals’ T cells. She reports in the December Journal of Clinical Investigation.
Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Md., agrees that the study shows T cell exhaustion. He cautions, however, that the results might not apply to people.
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Pat Fast, IAVI’s medical-affairs director, says Ertl’s mouse findings “may well be an effect of a very high dose” of the vaccine. She adds that the study’s relevance to human trials remains “unclear” and that a new, unpublished monkey study of the vaccine found no evidence of T cell exhaustion.
In September, NIAID and Merck & Co. of Whitehouse Station, N.J., stopped a large clinical trial of an HIV vaccine that used a different genetically modified virus. An early analysis found that the vaccine may have inadvertently increased susceptibility to HIV infection. This vaccine used an adenovirus—not an adeno-associated virus—to deliver pieces of HIV to the volunteers.
Fauci says he’s worried that the similarity in the viruses’ names will lead people to conclude that T cell exhaustion caused the anomalous mouse results in the halted Merck trial. “There is a major difference between adeno-associated virus vectors and adenovirus vectors,” he says. Investigators are now trying to sort out why the adenovirus vaccine didn’t work, says Fauci.
Of some 30 HIV vaccines that have been developed, none has yet proved effective in preventing infection or slowing HIV transmission.