Understanding the Complexities of Adenoviral Vector Vaccines

What are the potential advantages and disadvantages of using vectors derived from the adenovirus—which causes the common cold—as vehicles for AIDS vaccine candidates?

Every vaccine prevents infection by teaching the body to detect and destroy the particular viral, bacterial, or parasitic pathogen it is devised to target. Many do so by presenting the immune system with weakened or killed versions of the targeted pathogen, thus instilling a lasting immune memory of the responses required to disable it. But such approaches are not favored in AIDS vaccine development: An incompletely killed batch of HIV could cause an incurable and potentially lethal infection. And, given HIV’s extraordinary mutability, there’s a substantial risk of similar consequences if a weakened virus were to spontaneously revert into a highly virulent form.

To circumvent these risks, scientists employ a range of genetic engineering tools to devise HIV vaccine candidates that contain fragments of HIV designed to elicit protective antibody or cellular immune responses but could never cause HIV infection. One such strategy relies on engineered viruses. These viruses, known as vectors, are weakened by researchers, so they are unlikely to cause disease. They are also manipulated so that, in addition to most of their own genes, they carry genes encoding fragments of HIV—the active ingredients of vaccines, known as immunogens—that might elicit protective immune responses against the virus (see VAX Sep. 2004 Primer on Understanding Viral Vectors and VAX Dec. 2007 Primer on Understanding Replicating Viral Vectors).

The Ad5 setback

One viral vector vaccine candidate that seemed particularly promising five years ago was derived from adenovirus serotype 5 (Ad5)—one of the many variants of the virus that causes the common cold. Unfortunately, the candidate, which was developed by Merck and known as MRKAd5, did not work in a large international efficacy trial named STEP (see VAX Oct.-Nov. 2007 Spotlight article, A Step Back?). That study also uncovered an unexpected and alarming phenomenon in a subgroup of volunteers: uncircumcised men who have sex with men (MSM) who had been naturally exposed to Ad5 prior to joining the trial and had generated antibodies to the virus in response. (Antibodies are large, exquisitely precise immune system proteins that latch onto viruses and other pathogens to neutralize them or tag them for destruction.) In this population, researchers found that volunteers who had been vaccinated with the MRKAd5 candidate had higher rates of HIV infection than those who had received the placebo. Five years after the STEP trial was stopped, scientists are still trying to determine why this was the case and have been reluctant to develop new candidates that employ Ad5 as a vector.

Researchers have found that pre-existing Ad5 antibody immunity from natural exposure to Ad5 appears to dampen cellular immune responses to the HIV proteins encoded by the vector.

For this reason, researchers are exploring the possibility of using other adenoviruses, such as Ad26 and Ad35, as vectors for HIV vaccines. They reason that people are less likely to have pre-existing immunity to these vectors because fewer people are exposed to the naturally circulating viruses on which they are based. These alternative adenoviral vectors also elicit immune responses distinct from those induced by Ad5.

Although adenoviruses aren’t the only vectors available for making AIDS vaccine candidates, researchers continue to study them because these viral vectors are known to induce strong immune responses. One recent study in nonhuman primates compared the effectiveness of different vaccines containing adenoviral vectors delivered in a heterologous prime-boost regimen—in which two different vaccines are delivered sequentially, weeks or months apart. Candidates built from alternative adenoviral vectors were more effective than those based on other vectors or DNA in protecting rhesus macaques from repeated exposure to relatively virulent strains of simian immunodeficiency virus (SIV)—the monkey equivalent of HIV. These prime-boost combinations were also associated with greater control of viral load by macaques that became infected with SIV.

Prime-boost regimens of alternative adenoviral vectors have also been found to be safe and immunogenic in early stage HIV vaccine trials. Several such trials are currently evaluating prime-boost regimens that include Ad26- or Ad35-based candidates (see VAX Jan. 2012 Global News and VAX Nov. 2010 Global News).

Lingering questions

It is still not entirely clear if these alternative adenoviral vectors will be free of the issues related to pre-existing immunity that compromised the Ad5 vector. For example, researchers recently found that many STEP trial participants don’t just have Ad5-specific antibodies, but also cellular immune responses to Ad5, and that even participants without Ad5-specific antibodies had such cellular responses.

They also found that, in participants of another trial that evaluated the MRKAd5 vaccine used in STEP, pre-existing Ad5-specific cellular responses recognize regions of the Ad5 virus that are shared by other adenovirus strains. That includes less common strains, in which—in theory—the risk of pre-existing immunity is not as great. Further, such cellular immune responses were associated with a dampened cellular immune response to the HIV immunogens encoded by the vector—a response essential to the efficacy of such vaccines.

This has raised questions about whether the same dampening effect will be found in vaccine candidates that use alternative adenoviral vectors, and whether that might diminish their efficacy. Some scientists suspect the effect may be negligible because the immune responses induced by prime-boost regimens of adenoviral vectors are so vigorous. So, at least for now, researchers plan to continue evaluating adenoviral vector-based HIV vaccine candidates in clinical trials.