HIV Update: Therapeutic and Preventive Vaccines

It is estimated that there are more than one million people in the U.S. living with HIV and 33 million people worldwide.¹ This number is expected to grow, in part because it is inevitable that some with HIV will transmit the disease to others, but also because treatments for those infected are improving and prolonging lives.

While growth in the number of new HIV infections likely will increase, some statistics show promising news that in recent years, that rate of increase is stabilizing. Newly transmitted infections have decreased dramatically since the 1980s when, at its peak, 92 out of every 100 persons with HIV transmitted the disease. But, by the year 2006, that rate dropped to approximately 5 percent, with 53,000 cases newly diagnosed. Today, it is estimated that 56,300 are diagnosed yearly.^2,3 Education efforts are largely responsible for this decline, with research showing that the majority who know they are infected with HIV will take steps to prevent transmitting the disease to others. There also have been dramatic decreases in the incidence of transmission between mother and child with anti-AIDS drugs.

However, other sources, such as the newly released World Health Organization worldwide study, show a troubling picture of AIDS as the leading pathogenic cause of death for women ages 15 to 44 years. Obviously, the impact and the burden of this statistic vary by world region.⁴

Prior to the introduction of antiretroviral medications, opportunistic infections (those that are more severe and frequent due to a suppressed immune system) were the leading cause of mortality and morbidity in HIV-infected individuals in the U.S. Today, these infections continue to be a significant cause of death. The HIV virus mutates rapidly, there are numerous subtypes, and there appears to be a limited window for a vaccine’s ability to stop or delay infection — perhaps within hours or days. But scientific prevention of the disease through new testing methods, as well as efforts to produce a vaccine for both prevention and as therapy, offer hope. Researchers are focusing on both the cellular and humoral response of the immune system, and as with many other vaccines, looking not only at prevention but at halting disease progression.⁵

Vaccine Research

The National Institute of Allergy and Infectious Diseases (NIAID) has supported more than 100 vaccine trials involving more than 60 different products. Dozens of those HIV vaccine candidates entered Phase I clinical trials in the last 15 years. And, while many of these produced a positive HIV immune response, few have proceeded to Phase IIa and Phase IIb trials.

STEP study. One of the better known studies in HIV vaccine research is the STEP Study, which tested an Adeno 5 (adenovirus type 5) vaccine candidate in 3,000 volunteers in the U.S., Latin America and Australia.⁶ However, the study was eventually stopped, explains Dr. Alan Fix, branch chief of Vaccine Clinical Research of the NIAID’s Vaccine and Prevention Research Program, “because a planned DSMB [data safety monitoring board] review of the data indicated that the vaccine neither prevented infection nor resulted in lower viral load among those who became infected.” He adds that results at the time also indicated more infections among those vaccine recipients who were Ad5 seropositive and uncircumcised compared to placebo recipients with those attributes.

Although the trial was stopped, scientists are still gleaning data from the study, such as mapping epitopes to determine their importance in the immune response, and will be continuing the analysis for potentially years to come.

Current research. Initially, the search for a preventive treatment looked for vaccines to produce an antibody response. When that approach didn’t appear to be successful, the focus turned to eliciting a cellular response. Fix explains that “the various types of vaccines previously and currently being explored include peptide, protein, DNA and viral and bacterial vectors.” While HIV vaccines under study do produce antibodies that can cause a positive test for HIV, more sophisticated tests can distinguish the vaccine antibodies from the actual HIV virus.⁷

Recombinant vector vaccines use attenuated non-HIV viruses as vectors to deliver copies of HIV genes into the body’s cells, allowing the body to use the instructions in the genes to produce HIV proteins, stimulating an anti-HIV response. According to the National Institutes of Health AIDS information fact sheet, “Some of the virus vectors being studied for HIV vaccines include ALVAC- (a canarypox virus), MVA- (a type of cowpox virus), VEE- (a virus that normally infects horses) and adenovirus-5- (a human virus that doesn’t usually cause serious disease) based vectors.”³

Research on the body’s production of antibodies as prevention is still under way as scientists work to identify broadly neutralizing antibodies that could create a multiple attack on an HIV virus. Several of these antibodies have been identified so far, and it is thought that these greater numbers of antibodies could broadly neutralize the virus even though it mutates.⁸

In November of 2009, the NIAID announced a new direction in generating HIV antibodies by focusing on a specific, vulnerable location on the non-mutating HIV surface protein gp120. By binding the HIV neutralizing antibody, b12, to the specific initial attachment site on the gp120, the immune system can be taught to effectively make HIV antibodies, binding to the functional viral spike, and forming a normal trimeric structure.⁹

Prime-Boost Vaccination

Researchers also are looking at the effectiveness of combining vaccine strategies. Called “prime-boost vaccination,” this technique stimulates different immune responses that may further protect against HIV infection.

RV144 Phase III. The RV144 Phase III study conducted by the U.S. Army and the Thailand Ministry of Public Health was the first to show an investigational vaccine that demonstrated an ability to protect against HIV infections.¹⁰ The RV144 Phase III HIV Vaccine Trial tested the ALVAC-HIV vaccine (prime), and AIDSVAX B/E vaccine (boost), the combination of which is based on common circulating HIV strains in Thailand.

More than 16,000 non-HIV infected volunteers participated in the study, half of whom received the prime boost and half of whom received a placebo. While all volunteers were HIV negative, all had an average risk of becoming infected. The study found that the prime boost combination group had a 31.2 percent lower rate of HIV infection compared with the placebo group, although the vaccine did not affect the amount of virus in the blood of those who became infected.¹¹ “The results were promising and scientists are working to understand their significance,” says Fix. “Scientists are determining the best use of the collected specimens in trying to identify a correlate for protection.”

HVTN 505 Phase II. Another Phase II NIAID study presently under way is the HVTN 505 that uses four immunizations of two investigational vaccines developed by NIAID scientists. The primer vaccine is a DNA-based recombinant and is given three times during an eight-week period, followed by one vaccination of a weakened Ad5-based recombinant vaccine that will help to stimulate the immune system.

The study participants are more than 1,300 circumcised HIV-free men between the ages of 18 and 45 years who have no circulating antibodies to the Ad5 virus. The study group, though not infected at the time the study began, is at a higher risk of infection. Researchers will look at what happens to viral load of those who become infected during the study and whether there is a lower rate of infection and a slower progression of the disease, as well as the safety of the two protocols.¹²

MTN 003 Phase II. A prevention tool currently being tested is a topical microbicide antiretroviral drug, tenofovir, in the form of a gel or cream applied to the vagina and oral tablets of tenofovir or a combination of tenofovir and emtricitabine known by the brand name Truvada. Both methods are used once daily.

Known as the VOICE (Vaginal and Oral Interventions to Control the Epidemic) study, the study of 5,000 uninfected women ages 18 to 45 in Africa began in September 2009 and will last approximately three and a half years. Scientists will be looking at which regimen, pill or gel, is followed more consistently, the frequency that study participants become infected, as well as the safety of the two measures.¹³ A companion study will look at the effects on bone mineral density, since an ongoing study has shown that tenofovir can have an adverse effect on both the spine and hip, though this effect has not adversely affected health.¹⁴

HIV Treatment

There are 31 FDA-approved antiretroviral medications in five separate classes on the market.¹⁵ These medications inhibit the HIV virus from fusing with cellular membranes (fusion/entry inhibitor); prevent the HIV RT enzyme from converting from HIV RNA into HIV DNA (reverse transcriptase [RT] inhibitors); prevent the HIV virus from producing infectious particles (protease inhibitor); or prevent the HIV virus from integrating into a target host cell (integrase inhibitor). To prevent the virus from developing a resistance to any one treatment, doctors like to use the fifth class of treatment, or a combination of two antiretroviral drugs, called highly active antiretroviral therapy (HAART). A medication that prevents the HIV virus from maturing also is being studied.

The Centers for Disease Control and Prevention’s newly updated Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents places a greater emphasis on effective antiretroviral therapy critical for preventing and managing infections.¹⁶

Quality of Life of the Infected

A number of studies aimed at improving quality of life and reducing infections in those with HIV are under way. Positive results show that while we wait for an approved therapeutic vaccine, infected patients will have options that improve their overall health and make HIV a manageable chronic condition.

Reducing tuberculosis (TB) in HIV positive patients with a booster vaccine. Lung infections are the biggest cause of death among those infected with HIV. A study conducted at Dartmouth Medical School found that a booster TB vaccination of Mycobacterium vaccae can prolong the life of those who also had previously received the Bacillus Calmette-Guérin (BCG) vaccine earlier in life. In the Phase III study of 2,000 participants in Tanzania over the course of seven years, the incidence of TB was reduced by 39 percent.

Improvements in visceralfat with tesamorelin. A serious side effect of HIV treatments can be abnormal fat distribution and abnormal lipid and glucose metabolism. 17 It appears from recent studies that tesamorelin, a growth hormone-releasing factor, can help patients improve their levels of visceral fat and waist circumference without having detrimental metabolic effects.

Two Phase III, randomized, placebo-controlled studies of more than 400 patients have shown the negative effects of increased blood lipids. The patients taking tesamorelin saw an 11 percent decrease in visceral fat and improvements in waistto-hip ratio, compared to only a .6 percent decrease in the placebo group. At the end of a six-month follow-up, the patients taking tesamorelin had an average 17.5 percent loss of visceral fat versus a loss of only 1 percent in the control group.

Reducing viral load. Studies have shown that those who have a reduced HIV viral load take longer to become sick and develop AIDS. It is also thought that those who have a reduced viral load will have less chance of transmitting the virus to others. These are just two of the reasons some scientists see viral load reduction as a key to reducing AIDS in the next decades.

Researchers at the South African Center for Epidemiological Modeling and Analysis (SACEMA) are proposing a voluntary mass testing of the most at-risk individuals and placing those found to be infected on a lifelong AIDS treatment of antiretroviral drugs. Early testing and treatment would be the key to long-term success.¹⁸

One Step Forward, Two Steps Back

The search for an HIV/AIDS vaccine has been one of the longest and most well-funded in history. Yet, at times, it has seemed to be one step forward and two steps back. However, building on previous studies, scientists are getting closer than ever to learning how the virus works and how it can be prevented and stopped. The search for a preventive cure and therapeutic treatment continues with growing promise.