HIV Vaccine Boost Induces Significant Antibody Response


An additional dose of HIV vaccine MVA-B four years after the last immunization induces significant immune responses in healthy volunteers, researchers from Spain report.

In an earlier trial involving healthy volunteers, three doses of HIV-modified vaccinia virus Ankara vector-expressing HIV-1 antigens from clade B (MVA-B) was safe, well-tolerated, and elicited moderate and durable HIV-specific T-cell responses in 75% of recipients and antibody responses in 95% of recipients.

Dr. Montserrat Plana from the University of Barcelona, in Spain, and colleagues in the RISVAC02boost study administered a fourth MVA-B boost four years after the last immunization in 13 of the original 24 vaccinated volunteers and analyzed the effect of this single-dose on the HIV- and vector-specific T- and B-cell immune responses.

Two and four weeks after the late MVA-B boost, about 45% of the volunteers had detectable HIV-specific CD4 and CD8 T cells, compared with only 12.5% immediately before the boost, according to the October 24 PLoS ONE online report.

 At four weeks, 80% had vaccine vector-specific CD8 T-cell responses, compared with 12.5% immediately before the boost. This responder rate declined to 50% at week 12.

HIV antibody responses peaked two weeks after the boost (with mean titers rising from 96.5 before the boost to 11,460) and subsequently declined to mean titers of 5,353 at week 4 and 1,946 at week 12.

Serum neutralizing activity against HIV-1 was negative in all volunteers immediately before the boost, but 10 of 13 volunteers (77%) were able to neutralize HIV-1 two weeks after the boost. Neutralizing-activity titers decreased until the end of follow-up at week 12.

All participants had at least one adverse event related to vaccination, but most events (96%) were grade 1 and only two (4%) were grade 2.

 “Our results show that one boost of MVA-B four years after receiving 3 doses of the same vaccine against HIV was safe, with more reactogenicity than previous immunizations,” the researchers conclude. “The late MVA-B boost induced moderate increases in the HIV-specific T-cell responses but significantly boosted the antibody responses to HIV-1 Env protein as well as the generation of HIV-1 neutralizing antibodies. Hence, MVA-based vaccines have the potential to be further explored as a suitable component of an optimal HIV vaccine regimen.”

HIV Vaccine Draws Renewed Interest


Studies will look to improve on ‘modest’ benefit of first successful drug.

Almost 7 years after the first evidence that an HIV vaccine is possible, researchers are launching a new trial hoping to improve on the 2009 results.

The vaccine used in the so-called RV-144 trial, conducted in Thailand, yielded modest protection — a reduction in the risk of HIV of about 31%. But it was enough to suggest that tweaking the vaccine might get a better outcome.

“We’re looking for ways — not just of repeating the trial — but of doing better,” commented Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases.
Dieffenbach, whose institute is deeply involved in HIV vaccine research, moderated a press briefing at the International AIDS Conference here where details of the new studies were given.
The RV-144 trial actually used two vaccines — a canarypox virus called ALVAC, engineered so it could not cause disease, and carrying the gag, env, and pro IUV genes. Volunteers were given four injections of ALVAC over 6 months or a matching placebo.
And at the last two injections, volunteers also got a shot of AIDSVAX B/E (which targets the HIV gp120 protein) or placebo — a vaccine candidate that had been tested on its own and found to be safe, but without benefit.
For the current studies, researchers first had to adjust vaccines to target proteins from clade C HIV, which is the type of virus that circulates in Africa, according to Linda-Gail Bekker, MBChB, PhD, of the Desmond Tutu HIV Centre in Cape Town, South Africa. The RV-144 vaccine was aimed at clades B and E, seen in Southeast Asia and elsewhere.

But they also added a new adjuvant to increase its immunogenicity and an extra booster shot at 12 months to the 6-month series of vaccinations used in Thailand, said Bekker, who is also president-elect of the International AIDS Society.
The tweaked vaccine has now been tested for safety and immunogenicity and been given the go-ahead for a full-scale efficacy trial in South Africa, Bekker told reporters.
To get the go-ahead, it had to pass four immunological criteria to show it would work better than RV-144, she said. In a phase II study dubbed HVTN 100 with 250 HIV-negative volunteers, she said, the vaccine candidate showed:
A high antibody response rate to the HIV env protein.
An env antibody response whose magnitude was at least as good as that seen in the RV-144 trial.
A powerful CD4-positive T cell response to env.
And an antibody response to the conserved region between the env V1 and V2 loops.
The vaccine candidate beat pre-specified levels for the go-ahead and also did markedly better than the RV-144 vaccine on all four, Bekker said.
The efficacy trial, HVTN 702, is set to start enrolling 5,400 people across South Africa, with the hope of showing at least a 50% vaccine efficacy, according to Glenda Gray, MBChB, president of the South African Medical Research Council, who will lead the trial.
Results should be available in 2020, she told MedPage Today.
While a 50% efficacy might seem small, Gray said, it’s likely enough to have an important effect on the HIV pandemic in places where there is a high burden of HIV. And it would only be the first step in an “iterative process” that she and others hope would lead eventually to even better vaccines.
And 50% is better than some versions of the annual influenza virus, commented Larry Corey, MD, of the Fred Hutchinson Cancer Research Center in Seattle, and principal investigator of the HIV Vaccine Trials Network, which is sponsoring the new studies.
An HIV vaccine had long been a mirage, Corey noted. At the 2000 AIDS conference here, “there was no mention of it,” he said.
Since then, the emphasis has been on improving treatment, spurred by the realization that HIV therapy is a powerful prevention tool as well as a life-saving intervention. But Corey said the world needs prevention tools “that are so generalizable that can be given to everyone.”
“The best way to do that is a vaccine,” he said.
Gray noted that a vaccine would also fill another need — prevention methods that can be controlled by women, who are often unable to insist their partners use such things as condoms.
“A vaccine is the ultimate female prevention tool,” she said. “You put it in your arm and it works in your vagina.”
While South Africa is gearing up for a trial of a fairly traditional vaccine, investigators are also looking a novel approach — using monoclonal antibodies against HIV to see if they can prevent transmission.
Corey said a study of the “broadly neutralizing antibody” VRC01 started in March in the U.S., South America, and Europe, aiming to see if it reduces the risk of HIV among a cohort of 2,700 men who have sex with men and transgendered women.

And a parallel study began in June in South Africa, aiming at enrolling 1,500 heterosexual women in seven sub-Saharan countries.
The so-called AMP trials, Corey said, are expected to have results by 2018.

Phase II Trial Offers ‘Proof of Concept’ for Therapeutic HIV Vaccine.


A peptide-based vaccine against HIV-1 reduces viral load set-point after combination antiretroviral therapy (cART), a new phase II trial demonstrates.

However, there was no difference between the vaccine and placebo groups in the study’s two primary endpoints, the proportion of patients who resumed treatment after cART interruption or CD4 cell count.

“We believe the study reported here provides initial proof of concept to support a role for therapeutic HIV vaccines, since the finding that Vacc-4x is immunogenic and capable of changing plasma viral load setpoint after an analytical treatment interruption of cART,” Dr. Richard Pollard of U.C. Davis Medical Center in Sacramento and colleagues stated in The Lancet Infectious Disease, in a paper online February 11.

Vacc-4x (Bachem AG, Bubendorf, Switzerland) targets domains on the HIV-1 core protein, p24Gag. The study, at 18 sites in the U.S. and Europe, enrolled 137 patients who were virologically controlled on cART, with data available for 135 patients.

Patients were given a dose of the vaccine weekly for the first four weeks of the study, and then booster immunizations at week 16 and week 18. Patients continued on cART for an additional 10 weeks, and then cART was stopped in individuals with a CD4 count above 350 x 1,000,000/L who were under virologic control. Patients resumed cART if their CD4 counts dropped below this level or fell to more than half of their levels at week 28; if their viral load went above 300,000 copies per mL on two consecutive measurements; or if they developed HIV- or AIDS-related events. The study ended at week 52, and patients were followed to week 104.

Thirty patients (34%) given Vacc-4x began taking cART again between week 28 and week 52, versus 11 patients (29%) on placebo (p=0.89). Time to resuming cART was a median 198 days in the vaccine group and 175 days in the placebo group (p=0.77).

At week 48, patients in the vaccine group had a viral load of 23,100 copies per mL, vs 71,800 copies per mL in the patients on placebo (p=0.025).

At week 52, median viral load was 19,550 in the vaccine group and 51,000 in the placebo group (p=0.041).

The vaccine was well tolerated, with most adverse events involving injection site reactions. Nine patients, including five in the vaccine group, had serious events.

“It is recognized that because of the smaller number of recruited participants than originally planned (137 vs. 345) and the use of additional analyses, done on a subgroup of participants who achieved a 52 week off-ART period, these data need to be considered as exploratory,” Dr. Pollard and colleagues write.

“It’s an encouraging first step,” Dr. Merlin Robb, of the US Military HIV Research Program at the Walter Reed Army Institute of Research in Silver Spring, Maryland, told Reuters Health. Dr. Robb co-wrote an editorial on the new study. “If we could arm the immune system to better control the virus after a period of suppression under drugs, then we might have an important avenue to improve treatment outcomes and possibly achieve a cure.”

He and his colleagues are currently conducting clinical trials of HIV vaccine in individuals in the acute phase of HIV infection, when it may be easier to reduce the reservoir of infected T cells, he added.

The SMART trial, which looked at the effect of interrupting cART in HIV patients, found that patients who interrupted cART therapy were actually at greater risk of side effects than those who continued on cART, Dr. Robb noted. Dr. Pollard and his colleagues attributed the difficulty they had recruiting patients to the current trial to the “climate after the release of the SMART data.”

But studies like the current investigation, which are seeking curative treatments, are different from SMART, which looked at management of HIV, Dr. Robb said. “We need to brace ourselves to do these treatment interruptions safely and carefully, because we don’t want to do any harm, but we also want to see if these interventions have any impact.”

Strain of HIV virus found in monkeys is cleared by vaccine.


Vaccine could be used on humans in clinical trials within two years

A vaccine designed to tackle SIV, the monkey equivalent of HIV, may have successfully cleared the virus from infected animals, paving the way for research into a HIV vaccine for humans. 

It was previously thought that both the human and simian immunodeficiency viruses could be managed with antiretroviral therapies, but not eradicated.

However, a study published in the science journalNature showed that of 16 monkeys exposed to the virus who were injected with a vaccine, nine appeared to be able to clear their body of the disease.

US researchers from the Vaccine and Gene Therapy Institute at Oregon Health and Science University are now hoping to use a similar approach to test for a vaccine equivalent in humans.

The team examined a strain of the virus called SIVmac239, which is up to 100 times more deadly than HIV.

Researchers first inoculated monkeys with the vaccine and then exposed them to SIV. The virus did not spread in over half of the inoculated monkeys, which usually die within two years of being infected.

The vaccine used a modified version of the cytomegalvirus (CMV), which belongs to the herpes family, to sweep through the monkey body and encourage the immune system to fight off SIV.

After being exposed to the virus, some monkey bodies began to respond by searching out and destroying signs of SIV. They remained clear up to three years after first being inoculated.

Prof. Louis Picker told the BBC: “It’s always tough to claim eradication – there could always be a cell which we didn’t analyse that has the virus in it. But for the most part, with very stringent criteria… there was no virus left in the body of these monkeys.”

However, he said the team were still trying to determine why the vaccine was only successful in nine monkeys.

“It could be the fact that SIV is so pathogenic that this is the best you are ever going to get”, he explained.

“There is a battle going on, and half the time the vaccine wins and half the time it doesn’t.”

Now, the team want to examine if the same technique could be developed and made safe enough to be successful in humans. Clinical human trials could start within two years if the vaccine is approved and the team receive permission from regulatory bodies, Prof Picker added.

Source: http://www.independent.co.uk

SAV001-H: HIV Vaccine Has No Adverse Side Effects In Early Trial.


We may be a step closer to a vaccine against HIV — with no bad side effects.

The vaccine, called SAV001-H, didn’t show any adverse side effects and also seemed to boost the body’s antibody formation against the virus, according to the first results released from Phase 1 trials, Discovery News reported. The vaccine was developed by researchers from the University of Western Ontario in Canada and Sumagen Canada.

According to a release on the Phase I trials from the university:

Sumagen announced today the patient enrollment has progressed smoothly and there have been no adverse effects observed including local reactions, signs/symptoms and laboratory toxicities after SAV001-H injection in all enrolled patients to date.

 

Now, the vaccine will go on to Phase II and III trials, which will show whether it is effective at actually making people immune to the virus that causes AIDS.

The Phase I study included adults ages 18 to 50 who have HIV; half were administered the vaccine, while the other half were given a placebo. The vaccine contained killed whole HIV-1 that had been genetically modified, researchers explained.

The study authors noted that this vaccine is unique in that it uses whole, killed virus, similar to polio and influenza vaccines.

This is not the only HIV vaccine in the works in the world. Spanish researchers are testing what is called the MVA-B vaccine, which was shown in early trials last year to reduce the power of HIV to a “minor chronic infection.”

 

Earlier this year, the Food and Drug Administration approved a pill to help prevent HIV in healthy people, called Truvada. The way it works is healthy people who may face a high risk of HIV — say, if their partner is infected — take the pill as a preventive measure to dramatically lower their risk of contracting the virus.

 

 

HIV vaccine ‘still a decade away’, say researchers.


An effective HIV vaccine may not be ready for another decade despite ongoing efforts by scientists around the world, AIDS Vaccine 2012 conference heard this week (9–12 September).

In 2009 a trial in Thailand, called RV144 and involving 16,000 volunteers demonstrated, for the first time, that a vaccine can protect against HIV infection in humans. The vaccine trial represented a milestone for HIV vaccine research: “until this point there was no proof of concept”, Bill Snow, director of the Global HIV Vaccine Enterprise, told the conference held in Boston, United States.

Further evidence of the vaccine’s effectiveness against HIV infection was published in Nature this week (10 September). Researchers examined the genetic sequences of HIV viruses in people who received the vaccine and those who received a placebo, and found the vaccine was most effective against HIV viruses with two specific genetic footprints.

“This was an independent confirmation of the efficacy of the vaccine,” Morgane Rolland, who led the research and is based at the US Military HIV Research Program, told SciDev.Net.

But despite the vaccine’s success, researchers are struggling to overcome research and manufacturing challenges, and say that the process of making it ready for roll-out is taking longer than expected.

Speaking at the Boston conference, Jerome Kim, who led the study in Thailand and is based at the US Military HIV Research Program, said: “We underestimated issues related to manufacturing [the vaccine product to be used in trials]”. Changes were made to increase the scale of the trial and guarantee the safety of the volunteers, prolonging the process.

In addition, researchers were not prepared for going to the next phase. The company that produced the component of the vaccine booster was small, and initially lacked capacity for producing the vaccine on a larger scale.

“The main reason for the delays in [further stage] RV144 trials is that they were not well prepared for success; nobody was ready for doing a follow-up study,” Snow told SciDev.Net.

Another reason for the delay was the decision to move later stage trials to South Africa, where the epidemic is severe. South Africa has more people living with HIV, estimated at 5.6 million, than any other country in the world, according to the Joint UN Programme on HIV/AIDS.

The trial in South Africa is expected to start next year, but scientists will need to adapt the vaccine for the particular HIV viruses circulating in the region.

“We have to be realistic on where the timeline will leave us; after three years of experience, we are less optimistic to have short-term results,” said Kim. “There is so much diversity [of the HIV virus], that it will never be possible to have a universal vaccine.”

Kim highlighted that a vaccine is unlikely to be ready before the next decade.

But Bruce Walker, a researcher at the Harvard University Center for AIDS Research and co-chair of the Boston conference, said “the HIV vaccine is a solvable problem, it is only an issue of human and funding resources”.

Source: http://www.scidev.net

 

Top 10 myths about HIV vaccine research.


Dec. 1 is World AIDS Day, and in commemoration of the occasion, the HIV Vaccine Trials Network, headquartered at Fred Hutchinson Cancer Research Center, debunks the top 10 myths about HIV vaccine research.

Myth No. 1: HIV vaccines can give people HIV. HIV vaccines do not contain HIV and therefore a person cannot get HIV from the HIV vaccine. Some vaccines, like those for typhoid or polio, may contain a weak form of the virus they are protecting against, but this is not the case for HIV vaccines. Scientists make HIV vaccines so that they look like the real virus, but they do not contain any HIV. Think of it like a photocopy: It might look similar, but it isn’t the original. In the past 25 years more than 30,000 volunteers have taken part in HIV vaccine studies worldwide, and no one has been infected with HIV by any of the vaccines tested – because they do not contain HIV.

Myth No. 2: An HIV vaccine already exists. There is no licensed vaccine against HIV or AIDS, but scientists are getting closer than ever before to developing an effective vaccine against HIV. In 2009, a large-scale vaccine study conducted in Thailand called RV144 showed that a vaccine combination could prevent about 32 percent of new infections. Researchers are starting to understand why this vaccine combination worked and how to improve upon it.

Researchers around the world continue to search for an HIV vaccine that is even more effective. Leading this effort is the HIV Vaccine Trials Network, the largest publicly funded group of HIV vaccine researchers in the world. The HVTN is an international effort to find a safe and effective vaccine to stop the spread of HIV. It is funded by the U. S. National Institutes of Health.

Myth No. 3: Joining an HIV-vaccine study is like being a guinea pig. Unlike guinea pigs, people can say yes or no to participating in research. All study volunteers must go through a process called informed consent that ensures they understand all of the risks and benefits of being in a study, and those volunteers are reminded that they may leave a study at any time without losing rights or benefits. The HVTN takes great care in making sure people understand the study fully before they decide whether or not join. All HVTN research adheres to U.S. federal regulations on research, as well as the international standards for the countries in which it conducts research.

Myth No. 4: A person must be HIV positive to be in an HIV vaccine study. Not so. While some research groups are conducting studies of vaccines that might be used in people who are already infected with HIV, the vaccines being tested by the HVTN are preventive vaccines. They must be tested on volunteers who are not infected with HIV.

Myth No. 5: Vaccine researchers want study participants to practice unsafe behaviors so they can see whether the vaccine really works. Not true. The safety of study participants is the No. 1 priority of HIV vaccine researchers and study site staff. Trained counselors work with study participants to help them develop an individual plan on how to keep from contracting HIV. Participants also are given supplies such as condoms and lubricant as well as instructions on how to use them properly. HIV efficacy trials enroll thousands of participants over several years, and with even with the best counseling some participants will still become infected through their risky behavior. Changing human behavior is never easy; after all, many people still smoke, even though it is widely known that smoking is the major cause of lung cancer. An AIDS epidemic would not exist if prevention was as simple as counseling people to change their risky behavior.

Myth No. 6: Now that there are pills that can prevent HIV infection, an HIV vaccine is no longer necessary. HIV-negative people who are at high risk can take antiretroviral medication daily to try to lower their chances of becoming infected if they are exposed to the virus. This type of therapy – called PrEP, short for PreExposure Prophylaxis – has been shown to be effective among those at high risk. However, it has not yet been recommended for widespread use. PrEP is unlikely to be an option for everyone because the pills are expensive and are not always covered by insurance, may cause side effects, and not everyone has access to them. Remembering to take a pill every day is also challenging for some people. The most effective way to eliminate a disease is by using an effective vaccine. It was a vaccine that eliminated small pox and has almost eliminated polio. Most likely it will be an HIV vaccine that eliminates HIV from the world. Vaccines are an effective, affordable and practical option.

Myth No. 7: An HIV vaccine is unnecessary because AIDS is easily treated and controlled, just like diabetes. While treatment for AIDS has dramatically improved over the last 30 years, it is no substitute for prevention. Current HIV medications are very expensive, and there are also many side effects. Sometimes people develop drug resistance and have to change the regimen of pills they take. Access to these drugs for the uninsured in the U.S. and those in the developing world is also very limited.

Myth No. 8: The search for an HIV vaccine has been going on for a long time and it’s just not possible to find one that works. The science of HIV-vaccine development is challenging, but scientific understanding continues to improve all the time. In just the past two years there have been promising results from the RV144 study in Thailand as well as exciting laboratory work, such as the discovery of new broadly neutralizing antibodies against HIV. HIV is a powerful opponent, but scientists are constantly learning from one another and using advanced technology to fight it. Science has come a long way in the 30 years since AIDS was discovered. In comparing preventive HIV vaccine work to other vaccine development, the time it has taken is not so surprising; the polio vaccine took 47 years to develop.

Myth No. 9: Vaccines cause autism and just aren’t safe. This is not true. Numerous studies in the past decade have found this claim to be false. The British doctor who originally published the finding about vaccines and autism has since been found to have falsified his data. There is actually no link between childhood vaccination and autism. It is true that vaccines often have side effects, but those are typically temporary (like a sore arm, low fever, muscle aches and pains) and go away after a day or two. The value of protection to vaccinated individuals and to the public has made vaccines one of the top public health measures in history, second only to having a clean water supply.

Myth No. 10: People who aren’t at risk don’t need an HIV vaccine. A person currently may not be at risk for HIV, but life situations can change along with disease risk. Such a vaccine also may be important for one’s children or other family members and friends. By being knowledgeable about preventive HIV vaccine research, a person can be part of the solution by educating friends and family about the importance of such research and debunking the myths that surround it. Even if a person is not at risk, he or she can be part of the effort to find a vaccine that will hopefully save the lives of millions of people worldwide. To learn more or find out how to get involved in an HIV vaccine study, please visit www.hvtn.org

Source: : Fred Hutchinson Cancer Research Center.

Fred Hutchinson Cancer Research Center
At Fred Hutchinson Cancer Research Center, our interdisciplinary teams of world-renowned scientists and humanitarians work together to prevent, diagnose and treat cancer, HIV/AIDS and other diseases. Our researchers, including three Nobel laureates, bring a relentless pursuit and passion for health, knowledge and hope to their work and to the world. For more information, please visit www.fhcrc.org.

source:Fred Hutchinson Cancer Research Center.

 

 

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