Janssen Vaccines & Prevention B.V., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, has announced results of a new study published in Nature which points to a potential new approach against human immunodeficiency virus (HIV-1) infection. The findings suggest that combining therapeutic vaccination with immune stimulation could be a potential way to achieve a so-called "functional cure" for HIV infection, a strategy to suppress HIV infection long term without the need for life-long therapy. The study was conducted by scientists at Beth Israel Deaconess Medical Center (BIDMC), the United States Military HIV Research Program (MHRP) of the Walter Reed Army Institute of Research (WRAIR) and industry collaborators, including Janssen and Gilead Sciences, Inc.

"Although we have made great progress in developing treatments that allow people living with HIV to live near normal lifespans, patients today have to be on pills every single day of their life for their entire lives," says Dr. Paul Stoffels, M.D., Chief Scientific Officer of Johnson and Johnson. "Our goal is to work across the entire continuum - to have a functional cure, which would keep patients' virus under check without the life-long burden of being on treatments, and ultimately, to have a preventive vaccine that stops HIV in the first place."

Typically, vaccines "teach" the body to rid itself of viral invaders by provoking an immune response. However, HIV attacks cells of the immune system. The virus kills the majority of infected immune cells but goes dormant in others. This reservoir of dormant, infected cells, where researchers believe HIV remains hidden during antiretroviral therapy (ART), is the primary reason HIV cannot currently be cured.

In this new study, conducted in non-human primates (NHPs) infected with simian immunodeficiency virus (SIV), a virus similar to HIV, the strategy was to draw the virus out of hiding with the goal of eradicating it from the body. Researchers combined two investigational therapeutic vaccines (an adenovirus serotype 26 vector vaccine (Ad26) and an MVA vector vaccine (MVA)) with a TLR7 agonist (an investigational drug that works on a protein of the immune system) into a treatment regimen to be administered alongside ART. When the treatment regimen was given to NHPs they achieved decreased levels of viral DNA in peripheral blood and lymph nodes, and improved viral suppression and delayed viral rebound when ART was stopped.

"The objective of our study was to identify a functional cure for HIV - not to eradicate the virus, but to control it without the need for ART," said lead author Dan Barouch, M.D., Ph.D., Director of the Center for Virology and Vaccine Research at BIDMC and Professor of Medicine at Harvard Medical School. "Current antiretroviral drugs, although they're lifesaving, do not cure HIV. They merely hold it in check. We are trying to develop strategies to achieve ART-free, long-term viral suppression."

In the two-year long study, researchers monitored the viral loads of 36 NHPs infected with SIV. After taking suppressive ART medicines for six months, the NHPs were given either the investigational Ad26/MVA vaccine alone (n=9), the investigational TLR7 agonist alone (n=9), or the Ad26/MVA vaccine/TLR7 agonist combination (n=9). A control group received no active treatment (n=9). To evaluate therapeutic efficacy of the vaccine and the TLR7 agonist, the researchers discontinued ART in all NHPs to assess viral load, viral load "setpoint" - the plateau in HIV levels seen in the absence of therapy - and the time to viral rebound.

"We found the combination of Ad26/MVA vaccination and TLR7 agonist stimulation more effective than either component alone," said Col. Nelson Michael, director of MHRP, who helped design the preclinical study. "This was especially striking in viral load set-point, which impacts the future course of the disease."

The nine NHPs who received the investigational vaccine/TLR7 agonist combination showed decreased viral load, and the virus was undetectable in three of the NHPs when ART was stopped. When compared to control, researchers saw viral set point that was 100-fold lower and observed a 2.5-fold delay in viral rebound. NHPs that received the Ad26/MVA vaccine alone demonstrated some viral load reduction, a 10-fold lower viral load set-point and a marginally delayed viral rebound. And the TLR7 agonist alone did not impact viral load or rebound in these NHPs that started ART during acute infection.

The investigational Ad26/MVA vaccine induced a robust immune response, both in magnitude (the number of immune cells generated) and breadth (the number of places on the virus the vaccine can target) in the preclinical study. Cellular immune breadth correlated inversely with set-point viral loads and correlated directly with time to viral rebound. This provides an immunologic correlate which could potentially be used to predict responses in humans, but this needs to be confirmed in human clinical studies.

Janssen, in collaboration with MHRP, recently began in-human studies to evaluate the potential of the HIV therapeutic vaccine in HIV infected patients who initiated ART during acute HIV infection. The Phase I/IIa study is evaluating the safety, immunogenicity of the Ad26/MVA vaccine regimen. The study will also explore the effect on viremic control after interruption of antiretroviral treatment following vaccination. The study will enroll patients who started ART during acute HIV infection and who are currently on stable ART.

The Ad26 vaccine is developed in partnership between the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH); BIDMC and Janssen. MHRP developed the MVA vaccine in collaboration with the Laboratory of Viral Diseases at NIAID/NIH. The TLR7 agonist (GS-986) was developed by Gilead. Funding for the study was provided by the U.S. Army Medical Research and Materiel Command and the Military HIV Research Program, Walter Reed Army Institute of Research through its cooperative agreement with the Henry M. Jackson Foundation (W81XWH-11-2-0174); NIH (AI096040, AI124377, AI126603); the Ragon Institute of MGH, MIT, and Harvard.

Article: Ad26/MVA Therapeutic Vaccination with TLR7 Stimulation in SIV-Infected Rhesus Monkeys, Dan H. Barouch et al., Nature, doi: 10.1038/nature20583, published online 9 November 2016.