Understanding Challenge Viruses

How does the choice of challenge virus affect the outcome of vaccine studies in nonhuman primates?

Before a vaccine candidate can be tested in humans, it is first evaluated extensively in both laboratory tests and animal models. Animal models help scientists gain important insights into human diseases and how to prevent them. Researchers also rely on animal models to help determine if a candidate vaccine is safe to administer in people.

In AIDS vaccine research, the most relevant animal model is nonhuman primates (NHPs), especially a specific species known as rhesus macaques. No animal can be infected with HIV—it is a pathogen specific to humans. But rhesus macaques can be infected with certain types of simian immunodeficiency virus (SIV), which is the monkey equivalent of HIV, or viruses known as SHIV that are constructed in the laboratory and contain parts of SIV and HIV.

The similarity between SIV and HIV allows scientists to mimic HIV transmission and infection in NHPs. They do this by purposely infecting the monkeys with batches of virus known as challenge stocks.

Researchers can also evaluate potential vaccine candidates by first giving the candidate vaccine to the monkeys and then exposing them to one of the challenge viruses. Studying the immune responses induced in the monkeys following vaccination, and how well these responses can protect against the virus challenge, can help researchers decide which AIDS vaccine candidates are the best ones to evaluate in clinical trials (see VAX October 2008 Primeron Understanding Animal Models of HIV Infection).

Different stocks, different results?

There are several different virus challenge stocks in existence and many variations are used in experiments evaluating AIDS vaccine candidates. There are notable differences between these virus stocks. This raises concern among scientists about whether the outcomes from studies that are conducted using different virus challenge stocks can be compared. This concern has led some researchers to focus on more thoroughly characterizing many of the virus stocks currently in use to better understand the differences between them. But some researchers think just knowing the differences between the multiple challenge viruses is not enough and instead suggest that all studies of AIDS vaccine candidates should be conducted with a standardized challenge virus to ensure that the results can be compared. Then, only those candidates that perform the best can be advanced to human testing.

The origin of virus challenge stocks

Most of the virus challenge stocks currently used in AIDS vaccine research are derived from a strain of SIV that naturally infected a nonhuman primate species known as sooty mangabeys. While sooty mangabeys don’t typically get sick when they are infected with SIV, rhesus macaques infected with SIV from sooty mangabeys develop a disease that is similar to AIDS in humans.

Because the quantity of virus isolated directly from a naturally infected animal is limited, researchers must propagate or “grow” more of the virus. This is usually done in a laboratory. Researchers can add the SIV to cells isolated from an NHP. Because viruses naturally reproduce when exposed to animal or human cells, researchers can use this procedure to produce more of the virus. While this technique solves the supply problem, it creates another potential problem. Propagating SIV in the laboratory can alter the properties of the virus stock. New batches of SIV that are cultivated in the laboratory can have genetic and biological differences. Conditions may also vary among different laboratories that are producing stocks of virus, which may also contribute to variability. So even though some challenge viruses may bear the same name, they could behave differently biologically, affecting the results of studies evaluating vaccine candidates.

Researchers have observed some practical differences between different virus challenge stocks. Some become more pathogenic after they’ve been cultivated in a laboratory, which means that they cause disease in NHPs much faster than the original challenge virus. Conversely, other viruses become more susceptible to antibodies, proteins that can bind to the virus and prevent it from causing harm, after they have been cultivated in the laboratory. Either way, these new batches of virus can impact evaluation of vaccine candidates.

While it is still unknown just how much of an effect these genetic or biological differences in virus stocks have on the outcomes of studies involving AIDS vaccine candidates, some scientists think they could be problematic. These researchers are therefore advocating for the development of a standardized challenge virus stock that everyone in the field can use to evaluate AIDS vaccine candidates in NHPs. However, even if this were to be endorsed by researchers, there is still some disagreement about what the best standard would be.

Meanwhile, researchers are also searching for new challenge strains whose biological properties more closely resemble HIV than the ones currently being used in NHP studies. For instance, one SIV strain now widely used in NHPs is harder to neutralize than HIV, making it difficult to test vaccine candidates that can induce neutralizing antibodies, so researchers have been experimenting with SIV and SHIV strains that can be neutralized more easily. Ultimately, improving the comparability of NHP studies of AIDS vaccine candidates will help researchers prioritize candidates that should be tested in humans.