Is There a Future for Effective Vaccines for Infectious Diseases?

The advent and widespread uptake of vaccines have led to great reductions in, and sometimes eradication of, some of the world’s most common and deadly diseases and viruses. However, progress has historically lacked when it comes to certain infectious diseases, including HIV and tuberculosis (TB). But, with continuous efforts being dedicated to developing effective vaccines for these infectious diseases, could there be a future for routine and effective HIV and TB vaccinations?

HIV

There has been a sense of scientific frustration when it comes to looking at the HIV prevention vaccine landscape, according to W. David Hardy, MD, adjunct professor of medicine, Johns Hopkins University. In an interview with The American Journal of Managed Care^® (AJMC^®), Hardy explained that the problem with developing an effective HIV vaccine has not been a lack of resources or funding but instead the scientific knowledge needed to unlock the code of how a person’s immune system could develop resistance to the virus.

While other viruses attack specific cells, the HIV virus attacks the immune system directly, resulting in damage to the immune system before it has the chance to create protection against the virus, he explained. According to Hardy, within 2 weeks of HIV infection, a person’s immune system is already compromised.

“We have to figure out a whole new and different way to stimulate the immune system to form resistance against a virus that human bodies have never done before,” he said.

One focus to better understand immune response to HIV has been to observe elite controllers, who are people infected with HIV but have undetectable viral loads without the use of HIV medication. However, just 1% to 2% of people with HIV are elite controllers, making them few and far between.

Until this point, there has been just 1 HIV prevention vaccine trial offering a glimmer of hope: RV144, also known as the phase 3 Thai trial. The study results of more than 10,000 people in Thailand were just on the border of being statistically significant, with the vaccine demonstrating a protective efficacy of 31% over 3.5 years. However, encouraging analyses have indicated that it was actually 60% in the first 12 months, explained James Kublin, MD, MPH, clinical associate professor in the Department of Global Health at the University of Washington, and executive director of the HIV Vaccine Trials Network (HVTN), in an interview with AJMC^®.

“So, the question is: How do we build on that 60% and increase and maintain a more durable response so that the protection lasts?” said Kublin. According to Kublin, there are 4 active trials that may turn this glimmer of hope into a reality, one of which is building on RV144.

• HVTN 702: This study is testing a new version of the experimental regimen that was first tested in RV144 among 5000 men and women in South Africa. The vaccine regimen consists of 2 experimental vaccines: a canarypox vector-based vaccine called ALVAC-HIV, supplied by Sanofi, and a 2-component gp120 protein subunit vaccine, provided by GlaxoSmithKline, with an adjuvant to produce an immune response. Participants will receive 5 injections over the course of a year.
• HVTN 704 and 703: Known as the Antibody Mediated Prevention Study, HVTN 704 is a phase 2b trial assessing the safety and efficacy of VCR01, a broadly neutralizing monoclonal antibody. The randomized, double-blind, placebo-controlled trial has enrolled 2700 men or transgender persons from the United States, Brazil, and Peru to receive either VCR01 or placebo every 8 weeks for 72 weeks. A parallel study, HVTN 703, has enrolled 1500 women in sub-Saharan Africa and will test the same vaccine. Both studies were fully enrolled in October, and results are expected sometime next year.
• HVTN 705: A collaboration between HVTN and Janssen, HVTN 705 is testing a vaccine in 2600 southern African women at risk for HIV, and enrollment is expected to be completed in the coming months. The vaccine regimen is utilizing Ad25.Mos4.HIV and aluminum-phosphate adjuvanted Clade C gp 140. Participants will receive 6 injections over 12 months.

“All 4 of these studies will be providing really critical results in the next 2 to 3 years and will really, I think, form the basis for how we get to a globally effective HIV vaccine,” said Kublin. He added, “It’s a very exciting time for HIV prevention at large and HIV vaccines, specifically, because of the different concepts that are being tested in the clinic against HIV infection.”

However, an effective vaccine for HIV treatment, and eventually a cure, is farther away. The approach typically taken is a shock and kill approach, where researchers try to wake up latently infected HIV cells and then effectively shock and kill them. According to Kublin, a lot of research needs to be done on the shock component and understanding how to target those HIV reservoirs that aren’t typically expressing the HIV antigens because they’re latently infected.

Tuberculosis

One fourth of the world’s population are infected with Mycobacterium tuberculosis, the bacterium that causes TB in humans. However, the majority of those infected have latent infection, and 10% are expected to progress to active disease at some point in their lifetime.

In areas of the world where the risk for TB remains high, infants are given the bacilli Calmette-Guerin (BCG) vaccine following birth to try and induce an immune response protecting against transmission from their parents. However, while the vaccine protects the infant from the most serious forms of TB through the age of 5 and has had a positive impact on mortality rates, it does not prevent actual infection. An infant can still become latently infected and even become actively infected later on in life if the immune system gets compromised.

“We need better vaccines that can have an impact on the prevalence of infection, that can reduce initial infection and/or reduce transmission, or just have an overall immunotherapeutic effect where if you gave it to someone that had latent infection, it can help the immune system clear infection,” said Daniel Hoft, MD, PhD, director of the Division of Infectious Diseases, Allergy and Immunology at the Saint Louis University School of Medicine, in an interview with AJMC^®. “But, we don’t know how to do that yet, and that’s an area of active research.”

In the past, many researchers believed that just one type of immune response was needed to fight against infection, and thus a large focus was placed upon leveraging T helper type 1 cells that secrete interferon-gamma and tumor necrosis factor. However, while those cells are important and are necessary for TB immunity, they are not the only cells needed to do so. As a result, vaccine candidates targeting just these cells came up short and researchers have been left struggling to identify what else is needed to induce an immune response.

Currently, one of the most notable vaccine candidates is ID93, a recombinant vaccine made from 4 proteins of mycobacterium tuberculosis that is given in combination with the adjuvant GLA-SE. According to Hoft, the different antigens that cover the different life stages of TB. The vaccine is being developed for use in people who have already received the BCG vaccine or have already been exposed to TB in order to prevent reactivation or reinfection. The vaccine has looked promising in several phase 1 and 2 studies. Most recently, the vaccine demonstrated safety and immunogenicity in a phase 2a clinical trial of 60 adults in South Africa who had recently been cured of infection with traditional therapy.

Currently, Hoft and researchers are conducting a phase 1 trial testing a freeze-dried, temperature-stable version of the vaccine in 48 adults in the United States. Typically, ID93 requires a temperature-controlled system when transported, which can be costly and not always feasible depending on the location. With a freeze-dried formulation, the vaccine can be distributed cheaper and more efficiently in low-resource settings.

According to Hoft, the vaccine has potential to be preventive for those who have not yet been exposed to TB, eliminate latent infection, and maintain latent infection in its latent phase so that it never progresses or activates.

There is also work in reinvigorating the BCG field, said Hoft. The vaccine does reduce the risk of infection currently, but not enough to impact the prevalence of TB. However, Hoft said, if researchers could identify how the vaccine reduces infection in some, it might potentially lead to an understanding of how to improve it.