The researchers from the medical school of Pittsburgh University used structural biology tools to describe “both the overall shape and the atomic details” of the architecture of the protein complex.
“This strategy allowed us to see both the forest and the trees,” explained study co-author Dr Peijung Zhang.
“Knowing what the CA (capsid) protein looks like and how the capsid is built will allow scientists to rationally design therapeutic compounds that interfere with assembly of the protein and affect its function.”
Senior author Dr Angela Gronenborn said: “Our lab experiments show that if we replace a few of the pivotal stitches in the seam by mutation, the resulting viruses are less infectious or even non-infectious.
“The capsid, and therefore the virus, can no longer function properly.”
Young scientists around their world are finding clues to crack the puzzle of what it will take to make an effective HIV vaccine.
Speaking at the AIDS Vaccine 2009 conference in Paris this afternoon they reported on pioneering work, most of which revolved around a type of cells known as denditric cells.
*Mathias Lichterfeld from Massachusetts General Hospital in Boston, US, explained: “Denditric cells are like the conductors of a concert. They are what get effector cells working: they prime T-cell (cellular) response and B-cell (antibody) responses.”
Elite controllers – a rare group of people who have HIV but keep it under control – have extremely effective denditric cells compared to other people with HIV or those who are HIV negative, his work has shown. “Manipulating denditric cells is an important element to any (HIV) vaccine,” he said.
*Jacques Bancherau from INSERM/Center for Human Vaccines in Texas, US, said his team was working on targeting and manipulating denditric cells, which he has been researching among cancer patients for 10 years.
“ One year ago we started injecting them into HIV patients and we have found this is safe. We need a proof of concept study on whether there is a future in manipulating these cells.”
He said if this proved to effective, it would be a “new methodology for HIV vaccine” that could be done anywhere off the shelf.
*Michael Liu from Oxford University said he was researching what happens to the T-cell response among patients very early on when they are infected. “We have found that T-cells have an effect on the virus in the early stages but that the virus can escape easily.”
*Sylvie le Gall from Harvard Medical School said her team was working on how the immune cells could improve their recognition of infected cells – research that could benefit the immune design of a vaccine candidate.
“We want to improve immune design. We want to improve the presentation of epitopes (a part of the virus surface that the body’s immune system targets for destruction) to evoke strong immune protection and to avoid epitopes that are useless.”
Six years ago there were no TB vaccines in trials and now there are 13 being tested in sites or clinics, Dr Jerald Sadoff, MD of the Aeras Global TB Vaccine Foundation, said this morning at AIDS Vaccine 2009 in Paris.
Now four AERAS-sponsored trials are currently taking place in Africa with two more in the pipeline for 2010.
UCT’s TB Vaccine Initiative (SATVI) with a human clinical trial site in Worcester and the Aurum Health Institute in Johannesburg are among its international partners currently engaged in trials.
Sadoff, who has been involved in the successful development of many vaccines, said that in Worcester: “On 15 July 2009 the first baby was vaccinated (with a new TB vaccine) in more than 80 years.”
He told the HIV vaccine researchers: “TB and HIV live together and they are an unholy marriage that is killing people. We do not like this and would like them to get a divorce.”
TB kills 1.77 million people per year and infects 9.27 million people around the world: nearly half a million those deaths and 1.5 million of these infections are among people with HIV, mostly in Southern Africa.
The death rate is much higher among people with drug-resistant forms of TB.
The existing TB vaccine, BCG, is among the most widely used vaccines in the world yet it is probably one of the most ineffective, Sadoff observed.
BCG, a routine vaccination for babies, is not safe for infants who are HIV positive.
Despite its limitations, Sadoff said, BCG still prevents about 70 000 deaths a year by playing a role in stopping the spread of TB among children.
US scientist Louis Picker announced encouraging results from a big monkey trial at AIDS Vaccine 2009 in Paris this morning.
The study found that 54% – 13 of the 24 rhesus macaques monkeys infected with SIV – showed complete control of infection after an initial viral “blip”.
And significantly for vaccine researchers, this research identified the type of immune cells with the capacity to completely suppress the monkey version of HIV (known as SIV).
The effector memory T-cells (CD8+ T-cells) seem to be powerful at blocking SIV at the early stage of infection as the virus enters the body.
This is a critical time for the body’s immune defence against HIV, as Dr Alan Bernstein, executive director of the HIV Global Vaccine Enterprise, explains: “It looks like the body has a narrow window of opportunity to stop HIV of hours up to a day or two.”
Picker said the cytomegalovirus (CMV) was known to be the best at triggering effector site-based T-cells. His team made three versions of a SIV vaccine using a modified form of CMV as the vector (vehicle to take virus particles into the body).
The form of CMV he used was replication competent vector (which means it can copy itself) and so far only non-replicating vectors have been used in human trials since they are safer.
Dr Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said scientists did not know if a non-replicating vector could produce these results and this was the “big punch” in Louis’s results.
A smaller study of this last year found that his type of vaccine protected a third of the 12 monkeys on which it was tested.
The results announced today are more significant since it is a bigger trial and all three groups showed “robust” responses, confirming that effector memory T-cells are providing protection (are the correlates of protection).
Picker said: “The effector memory control was abrupt (immediate), seemingly stable and correlates to CD8+ T-cells.”
The way in which the immune responses protect the body is a major, and complex, question for HIV researchers.
Bernstein said: “This reseach is very important for two reasons: understanding the correlates of protection is critical and we should be looking to see if effector memory T-cells were activated in the Thailand and STEP trials.”
Scientists do not yet know how the RV144 vaccine tested in Thailand provided partial protection (31%). The standard assays (lab tests) they do to test immune strength were discouraging yet the vaccine had some positive results – so they must now discover why.
Picker said an effective vaccine could combine neutralising antibodies, plus a CMV vector, and prime-boost vaccine (to boost the effect).
He is director of the vaccine programme at the Oregon Health and Science University’s Vaccine and Gene Therapy Institute in the US.
Dr Glenda Gray, director of the Wits Perinatal HIV Research Unit, today presented an “interim efficacy” analysis of data collected in the South African Phambili HIV Vaccine study.
This human clinical trial was halted in September 2007 due to futility (not showing efficacy) found in its companion study known as the STEP study. Both these trials were set up to test the same vaccine, the Merck Adenovirus 5, in uninfected adults.
Concern was raised at the time that uncircumcised men, who had pre-existing immunity to the Adenovirus 5, could be at slightly raised risk. But subsequent analysis of the STEP and Phambili data and follow up presented today showed that this was not in fact associated with increased risk of being infected. In the Phambili trial less than 20% of the participants had no pre-existing immunity to Ad5.
The trial was run in five provinces in South Africa with sites in Gauteng, North West, KwaZulu-Natal and the Western Cape and patients were followed up after September 2007 (data was frozen in August 2009).
Among the major findings that Gray presented were:
*This vaccine did not protect against HIV and there were no difference in new infections between the vaccine and placebo groups by the time of the first vaccination;
*But good cross clade immune reactivity was demonstrated: the vaccine being tested was a sub-type B candidate in an area where sub-type C is most common, but this finding shows at four weeks after two injections most volunteers had developed an immune response to both clades B and C (for clade C the response rate was 77%);
*A reduction in HIV viral load among the women who received the vaccine: 0.57 log reduction in viral load at the set-point (measured at the start of the study);
*early differences in CD4 decline between the vaccine and placebo participants: CD4 counts indicate immune strength so a slower decline is advantageous and over 12 months the vaccine group experienced this benefit but it was not sustained over time;
*Risk reduction behaviour was sustained over time; and
*Good uptake of male circumcision post-enrolment of about 32%: medical male circumcision reduces the risk of a man acquiring HIV by about 60% many studies have proved.
The new HIV infection rate that Gray reported was roughly 4% – about 10 to 20 times higher than the infection rate in the Thailand trial which was conducted among a low-risk population.
The number of vaccinations received did not impact on the probability of acquiring HIV (no statistical difference was found). During the trial 60 volunteers were infected – 40 of them were women.
Two-thirds of the volunteers got two vaccinations and a quarter got only one shot before the trial was suspended.
An update on clinical trials in the first plenary session at AIDS Vaccine 2009 today showed that more effective HIV vaccines are in the pipeline than any that have been tested before.
Gary Nabel, director of the Vaccine Research Centre at the US National Institute of Allergy and Infectious Diseases, said: “We have exciting new candidates that are eliciting response that have not been seen before.”
He told the packed hall that the HIV Vaccine Trials Network is currently testing a product that has shown great promise immunologically – in the lab delivering a “robust” response in stimulating CD4 cells and antibodies.
The HVTN 505 trial is testing a multiclade (includes different sub-types of HIV) DNA vaccine with an Adno booster (intended to stimulate the immune system). This Phase II trial started this year and will wrap up in 2012.
He also described new concepts around T-cell vectors (vaccines that stimulate cell-mediated immune response) and said this field was making advances. In particular he reported on the efficacy of the LCMV (a type of virus) at stimulating a powerful immune response in lab tests and he talked about a new generation of vaccines using the “mosaic” concept.
“On the T-cell side we can look forward to a lot of improvements,” he indicated.
Nabel said progress has been made on stimulating antibody immunity, guided by the analyses of blood from people who successfully generate broad neutralising antibodies.
“These individuals can serve as a guide to vaccine development,” he said.
Nabel emphasised the need to find new ways to measure immunity that will correlate (show a link to) protection against HIV and the important the window of opportunity to stop HIV as soon as it infects the cervix.
The long-awaited full results of the Thailand RV144 vaccine trial, presented at AIDS Vaccine 2009 in Paris this morning, yielded nothing unexpected.
The data and report, published in The New England Medical Journal today, confirmed what is already known: the vaccine had a modestly protective effect (31% efficacy compared to the placebo), was safe and well tolerated.
The trial investigators stood by their announcement last month that the effect was statistically significant – which has been a topic of much controversy in the last few weeks. One of their main points was that the statistics should be measured against the design of the trial and they explained why.
Colonel Nelson Michael, director of the US Military HIV Research Program, who presented along with Supachai Rerks-Ngarm, from the Thai Ministry of Health, Thailand, said: “This is the first evidence that a prime-boost HIV vaccine regimen may prevent infection and represents a significant step forward for vaccine research.
“While it will not likely have any immediate public health benefit, we are hopeful that the findings will guide additional studies and accelerate research efforts toward a more effective vaccine.”
Scientists at the plenary commented that the cellular immune results, released today, were what they had anticipated, and that important antibody tests had not yet been done so they could not comment on the vaccine’s ability to boost the humoral immunity (antibody immunity).
In summary, researchers still have no immunological clues as to why this vaccine was partially successful and this is one of the major questions that they will investigate now.
On the other hand, much of the data Dr Glenda Gray, director of the Wits Perinatal HIV Research Unit, presented from the interim analysis of the Phamibili study in South Africa (which was suspended in September in 2007 for showing no effect) was made public for the first time.
The excitement that abounds among many of the 1100 delegates at AIDS Vaccine 2009 in Paris this year is tangible. In just 12 months, since the last annual conference in Cape Town which was excellent, the field has experienced many encouraging developments.
The most well known of these are the preliminary results of the Thailand vaccine trial released last month. The statistical significance of these results is controversial but whatever the majority concensus, this is the first human clinical trial to show some protection against HIV.
All eyes will be on the release of the full data of this Thai Phase IIb trial for the first time tomorrow and presentations dealing with the immunogenicity and questions that these raise, among others.
From all accounts the immunogenicity results are not significant yet the vaccine had a modest success, suggesting that another marker is needed to know which HIV vaccines will be safe and effective. The follow up analysis to the Phambili trial in South Africa will also be presented.
Meanwhile Swedish researchers are reporting a small vaccine study in Tanzania has shown even better results than the Thailand trial, and their findings could be another positive development.
Another fascinating topic is the research on the elite controllers – a very rare group (about 0.5%) of the population who manage to keep their HIV viral load under control and CD4 counts high despite being infected. A handful of them have been identified in South Africa so far in KwaZulu-Natal.
A number of scientists attending this conference are studying their genes and searching for clues on how they do this, in order to inform improved vaccine designs in future.
A more controversial topic is whether it is time to take more risks in the type of vaccines being made, for example, to use viral-replicating vectors instead of sticking in the safer zone of non-replicating vectors.
The delivery of vaccines also seems to be important with in vivo electroporation giving better results than normal delivery. This could be an effective way to deliver a DNA vaccine against HIV.
That’s not all but my head is reeling and it’s time to do a report on the opening session of the conference that has just ended for The Times online.
Dr Alan Bernstein, the executive director of the Global HIV Vaccine Enterprise (one of the conference hosts with the National Agency for Research on AIDS and Viral Hepatitis in France) told the opening session: “This week we will hear very exciting and very important new data that holds great promise for the field and for the world.”
But he warned, as did other HIV leaders, that lack of funding threatens to derail the current momentum.
I will send reports to The Times as well as posting updates throughout the next three days until the conference closes on Thursday.
The AIDS vaccine conference in Paris next week will attract worldwide attention after the release last month of the encouraging results of the Thai vaccine trial.
The full results of the trial – which found infection rates were nearly a third (31%) lower among volunteers who received the vaccine than those who received the placebo – will be scrutinised at AIDS Vaccine 2009.
Questions have been raised about the study’s confidence intervals and how two ineffective vaccines produced a significant result. These questions are sure to be answered, although the details about how the vaccine works will take longer.
Another exciting issue on the agenda is the role of antibodies and scientists, including South African delegates, will be presenting the latest research on new antibodies.
The first AIDS vaccine conference was held in Paris in 2000 and the organisers of this year’s conference – the French National Agency for Research on AIDS and Viral Hepatitis and the Global HIV Vaccine Enterprise – say on their site is is “more evident than ever that a strong emphasis on basic research, within a creative and interdisciplinary context, is essential to find an effective vaccine to protect against HIV”.
I’m flying to France tomorrow night to cover the conference and will provide updates on this blog.