Investing in Surprise

Efficacy trials may be costly, but some researchers argue that they are the best way to advance AIDS vaccine research and development

By Regina McEnery

It was two years ago that the AIDS vaccine field, stung by the disappointing results of the STEP trial that showed Merck’s adenovirus 5 (Ad5)-based vaccine candidate (MRKAd5) had no effect, called for basic discovery research to become a higher priority (see Balancing AIDS Vaccine Research, IAVI Report, Mar.-Apr. 2008). The shift from clinical development to basic research was endorsed by the National Institute of Allergy and Infectious Diseases (NIAID), the leading funder of AIDS vaccine research, which also partly funded the STEP trial.

Yet despite a broad scientific consensus that the best and possibly only way to develop an AIDS vaccine is to try and solve some of the key biological questions that have hindered progress, the recently completed RV144 trial spurred many researchers to emphasize the unique and important value of clinical research. The RV144 trial, which tested Sanofi Pasteur’s canarypox vector-based candidate ALVAC-HIV (vCP1521) and AIDSVAX B/E (the genetically engineered version of HIV gp120 originally developed by VAXGEN), resulted in the first evidence of vaccine-induced protection against HIV (see Raft of Results Energizes Researchers, IAVI Report, Sep.-Oct. 2009).

Difficult to execute, sometimes controversial, and, until RV144, lacking any hint of efficacy, the handful of AIDS vaccine efficacy trials conducted over the years have raised new questions and caused some researchers to reconsider what is required for vaccine-induced protection against HIV. “Truth is, the only way we are learning what actually works and what doesn’t is from efficacy trials,” says Larry Corey, a University of Washington AIDS researcher who heads the HIV Vaccine Trials Network (HVTN) created by NIAID. “We have to continue doing them.”

This sentiment is shared by researchers who aren’t principally involved in conducting clinical trials. Norman Letvin, a professor of medicine at Beth Israel Deaconess Medical Center whose research involves nonhuman primate studies of HIV vaccine candidates, echoed the importance of clinical research in a recent commentary in Science magazine (1). “The results of the Thai trial underscore the extraordinary importance of also performing focused human clinical trials of vaccine strategies,” Letvin wrote. “Just as the recent failure É in the STEP trial could not have clearly been predicted based on the preclinical experiments that had been carried out, the findings in the Thai trial were not expected based on preclinical studies and human immunogenicity data.”

The results of the 3,000-person STEP trial illustrate how difficult it is to faithfully recapitulate HIV infection in animal models. The vaccine candidate had been successful in lowering acute viral load in macaques challenged with a hybrid simian/human immunodeficiency virus (SHIV) strain (SHIV-89.6P), but a similar effect was not observed in humans (see Getting It Right Early, IAVI Report, Sep.-Dec. 2007). The results of the RV144 trial also took researchers by surprise because the immunogenicity of the two vaccine candidates in earlier clinical trials was one of the main points a cadre of leading scientists used to argue against the launch of this large trial.

“We have learned to expect the unexpected in our efforts to generate an effective HIV vaccine,” wrote Letvin.

Economies of scale

Clinical discoveries, although incredibly useful, don’t come cheap. It is estimated to cost about US$500 million to develop a new vaccine. Since the turn of the century, the pace of vaccine research and development has quickened—there are now more than 80 vaccine candidates in the pipeline, and about 30 of them target diseases for which there are no vaccines currently available, according to the third edition of the State of the World’s Vaccines and Immunization (www.who.int/immunization/sowvi/en). By the end of 2008, the total number of vaccines on the market reached 120, making this decade the most productive ever in the history of vaccine development.

Large-scale efficacy trials are one piece of the extensive preclinical and clinical testing that is required to bring a vaccine to market. Because of the thousands of volunteers that need to be identified, screened, recruited, and tracked over the course of these long-term trials, later-stage trials also tend to be one of the most expensive links in the vaccine development chain. About 90% of the $130 million that the company VAXGEN invested in AIDSVAX—a gp120 protein vaccine candidate that was originally developed by the biotechnology company Genentech—was spent on two separate, but simultaneously conducted, Phase III efficacy trials, according to Don Francis, founder of VAXGEN, who is now director of Global Solutions for Infectious Diseases, a San Francisco-based non-profit organization that holds the intellectual property rights to AIDSVAX. These studies enrolled close to 7,500 men who have sex with men (MSM) and injection drug users from North America, Thailand, and The Netherlands. The RV144 trial, which enrolled about 16,000 participants and lasted six years, cost $105 million, less than its projected cost of $119 million.

Vaccine efficacy trials can be notoriously large and expensive for other diseases as well. Rotavirus, a common cause of diarrheal disease, which kills 500,000 children annually in the developing world, is a prime example of how much it can take to get a vaccine to market. Two huge Phase III trials, which each enrolled at least 60,000 infants from Europe, the US, and Latin America, were conducted to test the efficacy of Merck’s Rotateq and GlaxoSmithKline’s Rotarix vaccine candidates. The trials were so large because they had to rule out a very minor safety concern with an earlier rotavirus vaccine that was pulled from the market. These trials were estimated to cost between $263 million and $394 million respectively (2). Both vaccines were ultimately approved by the US Food and Drug Administration.

Aeras Global TB Vaccine Foundation, which currently has four tuberculosis vaccine candidates in clinical trials in Africa and two other candidates expected to enter clinical testing next year, estimates it will cost about $120 million to conduct a Phase III licensure trial of a single candidate. And the Health Policy Division of the George Institute for International Health in London, which studies product development issues surrounding neglected diseases in poor countries, estimated in 2006 it would cost between $85 million and $95 million for a Phase III malaria vaccine trial of 15,000 individuals. There is currently no vaccine against the insect-born disease, which is endemic in more than 100 countries and claimed about a million lives in 2006. A Phase III trial of malaria vaccine candidate RTS,S/AS01 was recently launched in Africa by GlaxoSmithKline Biologicals.

Other biomedical interventions against HIV can also be costly to evaluate in clinical trials. A Phase IIb microbicide trial of 3,099 women in Africa and the US known as HPTN 035 that found modest, though not statistically significant, benefit in reducing HIV transmission cost $90 million, while a Phase III trial of 9,385 women, known as MDP 301, which tested the same microbicide candidate in Africa and determined it was not effective cost $64 million. HPTN 035 had a 30-month follow-up period for volunteers, compared to a 12-month period for MDP 301, which contributed to its higher cost. HPTN 035 also cost more because it tested two different microbicide candidates, involved clinical trial sites on two continents, and involved more specimen collection.

But not all HIV prevention trials are this large or expensive. Three recent Phase III trials in Uganda, Kenya, and South Africa that evaluated the impact of adult male circumcision on reduction of HIV infection enrolled more than 11,000 men and cost less than $30 million, says Robert Bailey, a University of Illinois epidemiologist who led the Kenya trial. All three trials were stopped early after infection rates were found to be significantly lower among heterosexual men 18-24 months after undergoing the surgical procedure compared to the uncircumcised group. “For less than $30 million we have an intervention that is at least 60% effective,” notes Bailey.

Of course, a one-time surgical procedure is less expensive than the cost of administering six shots and collecting multiple cell samples, as was the case in RV144. “The repeated analyses of immune responses would add to the cost of a trial,” acknowledges Bailey.


Total Investment in HIV Vaccine Research 

Money spent on pre-clinical and clinical research has declined in recent years, while dollars for basic research have increased, reflecting the shift in resources toward solving some of the key scientific problems impeding the development of an improved pipeline of AIDS vaccine candidates. The HIV Vaccines and Microbicides Resource Tracking Working Group, which collected the figures shown below, will be releasing their 2009 numbers for total HIV vaccine investment later this year.

Determinants of cost

Not surprisingly, the single biggest factor that drives the cost of a vaccine trial is the number of enrollees. The more people that need to be recruited and screened, and the more volunteers that need to be tested, evaluated, and monitored over several years, the more it costs to run the trial. Jerald Sadoff, formerly chief executive of Aeras and now chief medical officer at the Dutch biopharmaceutical company Crucell NV, says the average total study cost per subject is about $7,700 for a Phase II or Phase IIb test-of-concept trial of a tuberculosis (TB) vaccine candidate, an estimate he based on an analysis of three TB vaccine studies. Based on this estimate, it would cost about $12 million to conduct a trial enrolling 2,200 individuals. Sadoff believes the calculations are probably about the same for an AIDS vaccine trial of similar size.

But there are numerous factors that can affect the cost of a prevention trial, notes Peggy Johnston, NIAID’s director of the Vaccine & Prevention Research program (see Trial Co$t). These range from the number of trial sites involved, the salaries paid to employees at the clinical research centers, the population that is being targeted, the exclusion and inclusion criteria, the frequency and complexity of specimen collection, as well sample shipping and storage.

“For instance, the MSM populations in US cities where there are vaccine clinical trial sites are fairly educated populations,” says Johnston. “They tend to be tuned in and have access to information so recruiters can reach them more easily. In contrast, high-risk black women tend to be more geographically spread out, especially in the southern part of the US. There seem to be no consolidated locations where recruiters can readily identify the hundreds if not thousands of volunteers that might be needed to meet enrollment criteria. This then would require additional sites and/or more staff to meet enrollment goals.”

Glenda Gray, director of the Perinatal HIV Research Unit at the University of the Witwatersrand in Soweto, South Africa, has worked on a number of different HIV prevention trials involving different populations. Serodiscordant couples are, by far, the most difficult and most labor-intensive to recruit and retain, according to Gray. “First you have to get the couples into your center and then the couples have to commit to staying together for the duration of the trial,” she says. “There is huge attrition along the way. I guess they yield important results, but they are really hard to study and find.”

Reimbursement of trial participants is also a factor that affects the cost of a trial. South Africa, for instance, has a policy requiring that trial participants be paid a flat rate for every trial visit. Advocates of the practice believe this encourages trial participation, but critics have argued that payments should be linked to actual time spent and expenses incurred per visit to prevent over-compensating, or under-compensating, participants (3). Jennifer Koen, a project researcher with the HIV/AIDS Vaccine Ethics Group at the University of KwaZulu-Natal, says that some kind of payment is typical in clinical trials, although they are usually framed as reimbursements for expenses and not a flat payment per trial visit as is the case in South Africa. “It seems that the setting of a standard payment for all site visits may not be the case in many developing countries,” says Koen.

Some researchers contend that international clinical trial networks such as the HVTN, which involve large groups of investigators conducting trials across multiple sites and countries, can also make trials more expensive. “Vaccine trials that are part of a larger network require a lot more coordination,” says Bailey. “There’s more bureaucracy, protocols need to be standardized, and there are multiple independent review boards. You are dealing with different communities and different leaders in the communities. I feel that these networks are often much more cumbersome and expensive than necessary.”

Corey disagrees. “The HVTN is every bit as efficient if not more efficient,” he says. “And aside from simple small Phase I trials, almost every HIV efficacy trial or larger trial is conducted at multiple sites.” Corey also thinks networks like the HVTN offer other advantages, including consistency. “The most important thing is that the data that comes out of a trial be interpretable within the context of the field. A network has a common lab, common structure, and brings some semblance of order from one trial to the next,” he says.


Trial Co$t  

A well-designed and executed clinical trial can provide important information that may lead to the design and development of improved HIV vaccine candidates. But clinical trials, particularly large-scale efficacy trials, don't come cheap. Below are some of the major factors that influence trial cost.

HIV Incidence
The lower the incidence of HIV in a target population or region, the more volunteers that must be screened and recruited for researchers to determine if the vaccine is effective in preventing or controlling HIV.

Recruitment and Retention
If a high-risk group is transient or difficult to reach, trial organizers often have to devote more money to recruit and retain them in a trial. To encourage retention, clinical trials may also provide payment to volunteers, either in the form of reimbursements for traveling expenses or as a fixed-rate payment for each study visit.

Inclusion and Exclusion Criteria
Exclusion criteria can drive up the cost of a trial. For example, after a post-trial analysis determined that pre-existing immunity to the adenovirus serotype-5 (Ad5) may have been an HIV risk factor for vaccinated, uncircumcised men who have sex with men (MSM) enrolled in the STEP trial, a subsequent trial using another Ad5 vector restricted enrollment to only circumcised MSM with no pre-existing immunity to Ad5. This affects the number of volunteers that must be recruited and screened.

Laboratory Specimens
Blood, cell, and tissue samples collected from volunteers are essential, but the volume and types of samples collected can both add to trial cost. Mucosal samples, for instance, are more complicated and time consuming to collect, and fewer laboratories are equipped to analyze them.

Equipment and Storage
Most specimens need to be stored and preserved properly in freezers, sometimes for years, for future analysis. When storage in an off-site laboratory is required, shipment of the samples under temperature-controlled conditions is necessary.

Manufacture of Vaccines
Manufacturing, testing, and supply of clinical-grade vaccines using well-defined processes in an appropriate Good Manufacturing Practices facility is critical for the conduct of efficacy trials. Cost can vary depending on complexity of the manufacturing process.


Sample collection

The collection and storage of laboratory samples is another one of the biggest expenses in conducting clinical trials, but is an area where researchers have some flexibility in how much they spend. RV144 trial investigators, for instance, were conservative in how many blood and cell samples they collected, partly to cut costs. They also limited the types of samples collected—no mucosal samples were collected in this trial. Francis says because RV144 was conducted in a low-risk population, scientists would have needed to collect mucosal samples from a large population in order to allow accurate comparisons of HIV-infected and uninfected volunteers. For that reason, the research team never seriously considered collecting mucosal samples, although this data may have proven instructive. “Considering the resistance from many sectors to undertake this study when it was proposed, we should all be grateful to those wise few who successfully pushed this study to fruition,” says Francis.

Myron Cohen, director of the Institute for Global Health and Infectious Diseases at the University of North Carolina, says the amount of sampling is crucial. “The decision is often made that it is prohibitive to collect biological samples,” says Cohen. “If it’s semen from a man or vaginal secretions, that’s a big deal. And if you collect the samples, then you have to spin them down and store them properly. It all adds to the cost.”

For instance, about half of the 500,000 blood samples collected during the course of VAXGEN’s two Phase III trials are being stored in 34 sub-zero freezers powered by generators the size of a large bedroom. Francis secured a grant from the Bill & Melinda Gates Foundation just to help pay for the preservation of the samples.

But if you ratchet down the sampling, says Cohen, you end up with the scientific equivalent of a flight data recorder minus any data. You won’t learn much about what happened, he said.

An economical study

Not surprisingly, some researchers and AIDS advocates have questioned the cost of efficacy trials, saying the money would be better spent on basic research. Not long after RV144 was launched in the fall of 2003, 22 top AIDS researchers questioned whether the trial should be conducted because the vaccines being used in the prime-boost regimen had performed poorly in previous trials (4).

So when the surprising findings were released by US and Thai investigators in September 2009, the US Army, which funded about a quarter of the study, made a point of complimenting the research team for coming in under budget at $105 million. “The Thais did a remarkable job on this. I think the word is heroic,” said Eric Schoomaker, the Surgeon General of the US Army. “They did a remarkable job of acquiring volunteers and conducting the trial almost flawlessly and did not spend as much money as we estimated it would take.”

Jerome Kim, deputy director of science at the US Military HIV Research Program, says the trial benefited from fruitful partnerships with the Thai Ministry of Public Health, which provided the use of its facilities, including laboratory space to process the specimens and clinic sites to screen and recruit volunteers, all free of charge. US Army and US National Institutes of Health (NIH) officials who worked on the trial were paid through their respective institutions rather than from RV144 funds, which also lowered the overall trial costs. Additionally, Sanofi Pasteur donated the ALVAC candidate. “In addition to providing a surprising conclusion, funding for the trial was leveraged by the different collaborators and this decreased the overall cost of RV144,” says Kim.

Still, not everyone agrees that the resources on RV144 were well-spent, even given the positive results. “The Thai trial used two vaccines, neither of which showed adequate pre-trial immunity, and claimed to show a modest (and questionable) efficacy,” says Ronald Gray, a professor in population and family planning at Johns Hopkins University.

But others, including Glenda Gray, believe these large-scale efficacy trials are incredibly important. “The only time we have learned about the effectiveness of these vaccines has been when they have been tested in large-scale human trials,” she says. “We are going to learn about safety and a little bit about immunogenicity in smaller trials but the big studies are the ones where we can begin to understand the biology of transmission. To scale back on those would be a tragedy.”

The role of partnerships

Pharmaceutical companies have been a primary driver in late-stage clinical development of candidates, including those tested in the RV144 trial. But industry’s role in AIDS vaccine research and development has been waning. According to the HIV Vaccines and Microbicides Resource Tracking Group, investments in AIDS vaccine research and development declined from $961 million in 2007 to $868 million in 2008—a 10% drop that was blamed largely on a 61% decline in commercial investments from the pharmaceutical and biotechnology sectors (seeVaccine Briefs, IAVI Report, July-Aug. 2009). About $170 million was spent in 2008 on clinical research of vaccines by all public and private funders (see box at right).

By far the largest funder of AIDS vaccine efficacy trials—and HIV prevention trials in general—is the NIH, which will spend about $3 billion on AIDS research in 2010 (see Despite Recession, New Funding Stimulates Scientific Research, IAVI Report, May-June 2009). NIAID funds most of the NIH-related AIDS research, from bench science to efficacy trials. NIAID split the cost of the STEP trial with Merck, which developed MRKAd5, paid 80% of the cost of RV144, and will be funding the entire cost of a recently launched Phase II trial known as HVTN 505 that is testing the safety and efficacy of a DNA/Ad5 prime-boost regimen developed by the Vaccine Research Center at NIAID (see Vaccine Briefs, IAVI Report, July-Aug. 2009).

HVTN 505, which is likely to cost about $45 million, is a scaled-back version of the Partnership for AIDS Vaccine Evaluation (PAVE) study, which initially planned to test the vaccine regimen in 8,500 people around the world at a projected cost of $140 million (5). The PAVE protocol team revised the original study following the results of the STEP trial, which showed an increased risk of infection in uncircumcised men with pre-existing antibody immunity to Ad5.

While VAXGEN sponsored two Phase III AIDS vaccine efficacy trials, some pharmaceutical companies have been reluctant to invest in AIDS vaccine research. Sanjay Gurunathan, associate vice president for clinical development at Sanofi Pasteur, the vaccine division of the sanofi-aventis Group, says there are many hurdles when it comes to vaccine development, and with an HIV vaccine, both the investment and scientific risks are large, making it that much more difficult.

James Tartaglia, vice president of research and development at Sanofi Pasteur, says the swirl of criticism surrounding the start up of RV144 was a “little nerve-wracking,” but Sanofi believed all along that the vaccine should be tested for efficacy and never considered backing out of the trial even when others suggested it should not go forward. “We weathered it,” he says simply. “After that, we just wanted to make sure we executed the trial according to international standards so at the end of the day we would have a result we could rely on, whether it was a plus, minus, or in between.”

Tartaglia and Gurunathan say AIDS vaccine research needs these productive partnerships between pharmaceutical companies and the public sector to move forward. “I don’t think one single entity can actually shoulder the burden of developing an AIDS vaccine,” says Gurunathan. “It has to be a collaborative effort and there have to be partnerships involved in order to be successful in the near future.” 

1. Science 326, 1196, 2009
2. Vaccine 27, 6627, 2009
3. S. Afr. Med. J. 98, 926, 2008
4. Science 303, 316, 2004
5. Science 321, 472, 2008