Preclinical Assessment of HIV Vaccines and Microbicides by Repeated Low-Dose Virus Challenges

Background: Trials in macaque models play an essential role in the evaluation of biomedical interventions that aim to prevent HIV infection, such as vaccines, microbicides, and systemic chemoprophylaxis. These trials are usually conducted with very high virus challenge doses that result in infection with certainty. However, these high challenge doses do not realistically reflect the low probability of HIV transmission in humans, and thus may rule out preventive interventions that could protect against “real life” exposures. The belief that experiments involving realistically low challenge doses require large numbers of animals has so far prevented the development of alternatives to using high challenge doses. Methods and Findings: Using statistical power analysis, we investigate how many animals would be needed to conduct preclinical trials using low virus challenge doses. We show that experimental designs in which animals are repeatedly challenged with low doses do not require unfeasibly large numbers of animals to assess vaccine or microbicide success. Conclusion: Preclinical trials using repeated low-dose challenges represent a promising alternative approach to identify potential preventive interventions. Trials of HIV vaccines in animals using repeated low- dose challenges of the virus are feasible and may be more true to life. Background: Before trials of medicines or vaccines are done in humans, most are tested in animals. There are many controversies about these animal trials, including whether they mimic the human disease accurately. In testing vaccines for HIV, animals are mostly given high doses of the virus, whereas in real life people are often repeatedly exposed to small amounts of the virus. No vaccine that has been tested against HIV prevents infection in animals. It is possible that some of this lack of success may be due to the design of the vaccine trials rather than the vaccine itself. What Did the Authors Do?: They wanted to look at experimental designs that allowed assessment of protection against infection with lower, and thus more realistic, doses of virus. Previously, researchers had suggested that many animals would be needed for this type of study. The authors wanted to see whether this was correct. They developed a model to test how well single and multiple low-dose experiments performed. They did this by simulating the experiments with doses of virus, assessing the results, and then repeating this procedure 100,000 times to estimate how valid a given experimental design was. What Do These Results Mean?: It may be possible to use these results to plan trials of vaccines in animals that mimic more closely the way that humans are exposed to HIV, and hence the results may be more reliable for human disease. Where Can I Get More Information?: MedlinePlus has a great deal of information on HIV: