An HIV vaccine made by Merck that failed in clinical trials may have increased the susceptibility of some trial participants to the AIDS virus, researchers reported last week. The findings have left scientists grappling with the problem of how to handle future trials of vaccines that use similar strategies to stimulate an immune response.
The trial was suspended in September, when preliminary analyses showed that the vaccine failed to protect participants against HIV (see Nature 449, 390 ; 2007). The vaccine consisted of three HIV genes carried by a weakened viral vector. Neither the HIV genes nor the vector, made from a common-cold virus called adenovirus 5, were capable of causing infection.
But it seems that trial participants who had a pre-existing immunity to adenovirus 5 were more likely to become HIV-positive if they received the vaccine. Among male volunteers who had high levels of antibodies against the adenovirus, 21 of 392 became infected in the vaccinated group, but only 9 of 386 were infected in the placebo group. The vaccine did not affect infection rates in men with no adenovirus-5 immunity.
The trial was not designed to examine the relationship between adenovirus-5 immunity and HIV infection, and researchers cannot say whether the result is statistically significant. But they can't ignore the findings, says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. The start of another HIV-vaccine trial has been pushed back several months to allow more time for scientific review, he says.
For now, researchers are trying to determine whether the vector is to blame or whether those with high adenovirus-5 immunity are at risk for unrelated reasons. Immunologists say it is also theoretically possible that vaccination in those with pre-existing immunity may have triggered an immune response that transiently boosted production of activated CD4 cells — the very immune cells that HIV infects.
That theory leaves several questions unanswered. For example, it is not known how long after vaccination the activated CD4 cells would have remained in the mucosal surfaces where HIV first gains entry, says Fauci.
Researchers are nevertheless concerned. One possible solution is to limit future trials of adenovirus-5-based vaccines to participants with very low levels of immunity to the vector, says Gary Nabel, director of the Vaccine Research Center at the National Institutes of Health in Bethesda, Maryland. But doing so would close off the trials to a large proportion of the population they aim one day to help: more than 80% of sub-Saharan Africans have significant levels of adenovirus-5 immunity. In addition to the planned HIV-vaccine trial, an Ebola vaccine in development also relies on an adenovirus-5 vector.
But at this stage in vaccine development, researchers are just looking for a proof of concept rather than a vaccine that can be put directly to use, says Lawrence Corey, lead investigator of the HIV Vaccine Trials Network. Alternatives to adenovirus 5 are being developed, and may be substituted once the efficacy of a vaccination strategy has been shown. Nevertheless, vaccine developers will face challenging decisions in light of the new data, he says: “Translating uncertain data into policy is always a difficult issue.”
但在疫苗开发的这个阶段，研究人员只是期望找到支持理论的证据，而非直接能应用的疫苗，HIV疫苗实验网络第一调查人 Lawrence Corey说道。腺病毒5的谨慎使用已被提出，而且一旦接种策略被证明有效的话，就可能取代腺病毒5了。然而，疫苗开发人员将面临挑战性决策，因为可供参考的资料有限，他说到：”把未凿的资料转变为策略本身就是一个困难的问题。