Study finds Vaccine with Envelope Alone can Protect Monkeys from SIV Challenge

A prime-boost vaccination regimen using just Envelope—the protein from which the spikes on the outer surface of the virus are made—suffices to protect rhesus macaques from infection by simian immunodeficiency virus (SIV), but does not affect viral load in monkeys that do become infected, according to a recent study (Journal of Virology 2012, doi: 10.1128/JVI.00599-12). In the study, researchers used a so-called heterologous challenge, which is considered more realistic because the challenge virus differs from the type of virus carried in the vaccine. 

A previous study by Dan Barouch at Harvard Medical School and colleagues suggested that Env is essential to the ability of a prime-boost vaccine regimen to protect monkeys from SIVmac251 challenge (Nature 482, 89, 2012; see Adenovirus Vectors: Promise and Possible Pitfalls, IAVI Report, Jan.-Feb.2012). But it was unclear whether Env is also sufficient to achieve protection. 

The new study suggests the answer is yes. “It’s the first time in a heterologous challenge model that Env alone has been shown to be necessary and sufficient for protection,” says Gary Nabel of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases, who led the study.  

The study has immediate implications for HIV vaccine design. “We can’t put an infinite number of things in [a vaccine], so we want to get the biggest bang for our buck for things that we do include,” says Nabel, adding that in that sense, the finding that Envelope alone is sufficient for protection implies that for a preventive vaccine, it might be more effective to include three different Envelopes and so expose the immune system to a greater variety of Env, than to also include other HIV antigens, such as the proteins Gag, Pol and Nef. 

Nabel’s team vaccinated 10 Indian rhesus macaques with replication-defective adenovirus serotype 5 (Ad5) vector carrying SIVmac239 Envelope. They followed up eight weeks later with a boost using a replication-defective lymphocytic choriomeningitis virus (LCMV) vector carrying the same Env. Six weeks later, they challenged the animals rectally with a weekly low dose of SIVsmE660 until they became infected, but no more than 12 times. As a control, they challenged 10 animals that were sham-vaccinated the same way, but with vectors that lacked the Envelope insert. 

The vaccine protected most macaques from infection: After up to 12 challenges, eight of the 10 control animals were infected (after a total of 47 challenges), but only three of the 10 vaccinated animals were infected (after a total of 99 challenges). This means that the vaccine significantly reduced the rate of infection per challenge from 17% to 3%. “It’s quite significant protection,” Nabel says. “It’s a little bit better than [what] we saw in our previous studies,” he adds, referring to a study last year where Nabel collaborated with Norman Letvin at Harvard Medical School, to show that a DNA/Ad5 prime-boost vaccine regimen containing SIVmac239 Gag, Pol, and Env as immunogens protected about half the animals from a similar SIVsmE660 challenge (seeResearch Briefs, IAVI Report, May-June 2011). 

Because some, but not all, vaccinated animals were protected, Nabel and colleagues were also able to determine immunological correlates of protection. They found that serum from the protected vaccinated animals was better at neutralizing the challenge virus stock (i.e. keeping it from infecting human peripheral blood mononuclear cells in vitro) than serum taken from vaccinated animals that got infected. This suggests that neutralizing antibodies to Env played a significant role in protection. 

“This is an important piece of science,” says Nelson Michael, director of the US Military HIV Research Program and one of the lead authors of the earlier study by Barouch and colleagues that showed that Env is required for protection from SIVmac251. “It confirms and extends Barouch et al. by explicitly showing that expressed Env alone is necessary and sufficient. While the use of E660 challenge is not as rigorous as the mac251 challenge that was used in Barouch et al., that the same acquisition impact was seen using these two different models is very encouraging.” 

The finding that a vaccine that only contains Env doesn’t lower viral load, Michael adds, is also consistent with the previous observation by Barouch and colleagues that cellular immune responses to Gag are important for controlling viral load through vaccination. To Michael, this means that to have both a preventative and a suppressive effect, a vaccine would need to carry both Gag and Env. “This reinforces the concept that a minimal HIV vaccine payload should include both Env and Gag,” he says. 

Michael adds that the observation by Nabel's team that Env-specific antibody responses were important for protection is consistent with Env-specific antibody responses being important for protection in the human RV144 vaccine trial, although it remains to be seen whether neutralizing or non-neutralizing antibody activities were more important for protection in both the nonhuman primate (NHP) study by Nabel and colleagues and in RV144. 

The study is perhaps the first NHP protection study in the HIV vaccine field that uses LCMV as a vector, Nabel says. He and his colleagues chose the Ad5/LCMV regimen for their challenge study because a comparison of immune responses to different prime-boost vaccine regimens in mice showed that the combination of Ad5 and LCMV gave the highest antibody response and a strong CD8+ T cell response. They also found that the regimen elicited a strong antibody and cellular immune response in rhesus macaques. 

Still, it’s unlikely that the Ad5/LCMV regimen will be moved forward into humans, Nabel says. Preexisting immunity to Ad5 is widespread and has led researchers to look for alternative Ad vectors, where this is less of a concern (see Adenovirus Vectors: Promise and Possible Pitfalls, IAVI Report, Jan.-Feb. 2012). Nabel, for example, is collaborating with the biopharmaceutical company Okairos to explore the use of chimpanzee adenoviruses such as chimpAd3 as vaccine vectors in humans. "If we move this forward into humans, it would almost certainly be in a chimp[Ad]3 [regimen]," Nabel says. “We are moving chimp[Ad]3s forward into product development for human trials.”  

Preexisting immunity is not an issue with LCMV, which has very low seroprevalence in humans, Nabel says. Still, for now, LCMV is unlikely to be part of a vaccine regimen to be tested in humans that contains chimpAd3. "We have other options to mix with chimp[Ad]3," Nabel says.