Almost 30 years after the discovery of the HIV, we are still struggling to develop an effective vaccine . This study reviews two vaccine trials, one involving polio and the other HIV, conducted 50 years apart. Despite obvious differences in science and historical periods, several lessons are identified with the potential to inform future HIV vaccine efforts.
The two trials
Beginning in 1954, a killed, whole-virus vaccine against poliomyelitis was tested in the largest public health experiment ever conducted [2,3]. The formalin-inactivated formulation, developed by Jonas Salk, attracted considerable controversy due to potential safety and efficacy concerns. The trial, which was completed in less than 1 year, involved 1 829 916 children, recruited across more than 211 sites, mostly in the United States. The vaccine achieved 80–90% efficacy against paralytic poliomyelitis and in 1955, it was licensed and released for immediate distribution.
Five decades later, the RV144 trial, which tested a prime-boost recombinant vaccine against HIV, was conducted among 16 402 adults in Thailand. Implemented between September 2003 and August 2009, the trial demonstrated a 31.2% efficacy in preventing HIV infection . Although the initiation of this trial was marred by controversy , and the initial results were received with considerable skepticism , the field ultimately accepted the results, especially after the publication of an immune system correlates analysis .
Lessons from the ‘1954 field trial of the Salk poliomyelitis vaccine’
Although the scientific challenges in developing an HIV vaccine are more difficult than those encountered in the development of a polio vaccine, several lessons can nonetheless be identified in order to accelerate the development of an HIV vaccine and they are listed as follows:
- Paradigms change, and ‘expert’ opinion can be wrong. Maintain an open mind and dare to explore innovative approaches that may not conform to current scientific orthodoxy.
- Basic science is essential, but it alone will not be sufficient to develop a vaccine. Science needs to be translated into products for clinical evaluation.
- Human data trump everything we do in vitro or in animals, and we need to be prepared to expect the unexpected. Even a small number of endpoints in clinical trials can provide important information with which to generate hypotheses for further scientific evaluation.
- As there is more than one way to develop protective vaccines, and no guarantee than anyone will work, different concepts need to be tested in parallel.
- Current preventive interventions can have a significant impact on reducing the incidence of HIV infections, but new tools (especially a vaccine) are needed to stop the epidemic altogether.
- Vaccine development does not exist in a vacuum, and its importance needs to be understood and supported by society. Sustainable political support over the long term is needed in order to build on current modest successes. Government funding and activities would benefit from the comparative advantages and flexibility of nonprofit and philanthropic organizations.
- Invest in the future by protecting the funding necessary for vaccine development, perhaps up to 10% of total investment in our response to the epidemic.
- Preparation for success can shorten the time between the development of a vaccine and its widespread use in public health programs, which could save billions of dollars and millions of lives.
Lesson 1: ‘expert’ opinion is not always correct; paradigms change
Simon Flexner, the first director of the Rockefeller Institute for Medical Research in New York, maintained that poliovirus gained access to the central nervous system directly via the nasal mucosa. His views on the strict neurotropism of the poliovirus dominated the field until the 1930s, when the virus was proven to also infect the intestinal tract. It is humbling to realize that the scientific concepts proposed by one the most famous scientists of the time were ultimately incorrect, and it can be argued that misplaced scientific authority may have actually delayed the development of an effective polio vaccine.
In the case of HIV/AIDS, much has been learned about its molecular biology and pathogenesis . Less is known about the immunological mechanisms that could mediate protection from infection or disease progression . The scientific community continuously debates the role that antibodies and cell-mediated immunity play and how those immune responses can be induced with experimental vaccines . Proponents of different vaccine concepts often defend their views with passion and vehemence. Likewise, a highly effective vaccine may need to interdict virus transmission at the portal of entry, dealing with both, free and cell-associated viruses .
How many of our current scientific paradigms on HIV will withstand the test of time? Perhaps an entirely new paradigm will be needed to finally guide us to the development of a highly effective HIV vaccine. It is essential to explore innovative approaches, and welcome – not dismiss – innovative approaches that may not conform to current scientific orthodoxy.
Lesson 2: vaccine development cannot advance more quickly than scientific knowledge
Twenty years before the Salk trial, two other polio vaccines were tested for efficacy in humans [12,13]. These vaccines, prepared from the spinal cords of inoculated monkeys, not only failed to protect against infection, but one of them actually caused paralytic polio, a setback that discouraged the testing of novel vaccines for the next 20 years. With the benefit of hindsight, we now realize that in 1935, the scientific knowledge necessary to develop a polio vaccine was simply not available , including the ability to grow the virus in tissue culture .
Today, we confront similar dilemmas in the search for an HIV vaccine. Do we have enough scientific information to prioritize product development over basic research? There is tension between the undeniable value of more scientific information and the urgency to develop a vaccine. The practical vaccinologist is challenged by the ‘complexity, redundancy, and over information (that) modern molecular biology has created’ that makes it difficult to ‘hear the tune amid the static’ .
After the 2007 unexpected lack of efficacy in the STEP trial, which tested an adenovirus-vectored HIV vaccine , there were calls to shift the emphasis of HIV vaccine research toward basic science [18,19]. However, the mood seems to have changed since RV144, with a renewed interest in conducting clinical trials.
Basic research has undeniable value, but it will not produce a vaccine by itself. The optimum balance between discovery and development is not easy to strike, but exclusive focus on either extreme of this spectrum is unlikely to represent the best strategy.
Lesson 3: be guided by data, especially from clinical trials wherein even small numbers can provide critical information
In the past, expert polio virologists and immunologists constantly argued about the scientific merits of different vaccine approaches, with a clear preference for a live-attenuated vaccine. Inactivated vaccines were considered to be lacking in scientific glamour. However, Salk based his approach on his previous experience with formalin-inactivated influenza vaccines  and safety and immunogenicity trials of his polio vaccine in some 15 000 children . The stalemate between proponents of attenuated and inactivated vaccines was broken when the leadership of the National Foundation for Infantile Paralysis decided to move ahead with the testing of the Salk vaccine. After all, an efficacy trial was the only way to find out if the vaccine works.
Among the 401 974 children who participated in the placebo-controlled arm of the Salk trial, there were only 143 diagnosed cases of paralytic polio: 110 in the placebo arm and 33 among the vaccinated children. These low numbers were sufficient to conclude that the vaccine was effective, although the results were received with some reservation. Thomas Francis, the director of the trial, cautioned that there was no single value for measuring vaccine efficacy. Rather, he believed, it depended upon a variety of factors, such as placebo-controlled versus observational groups, paralytic versus nonparalytic, laboratory confirmation, study site, age of the volunteer, and poliovirus type.
In a scenario that was reminiscent of some of the heated discussions of the past, in 2004, a group of prestigious HIV scientists expressed opposition to the conduct of the RV144 trial. They argued that better vaccines were already in early-phase clinical trials . However, the vaccine tested in the RV144 trial ultimately produced modest efficacy, contrary to the STEP trial, which was a favorite of the scientific community [17,22].
In the RV144 trial, a total of 125 HIV infections occurred among the 15 948 patients selected for intent to treat analysis: 74 in the placebo arm and 51 among the vaccine recipients. Due to the small number of endpoints, the statistical analysis was initially dismissed by some critics.
Every time we conduct an efficacy trial of HIV candidate vaccines, surprising information is obtained that forces us to change the prevalent scientific paradigm. Human data trump everything we do in vitro or in animal models . We need to be prepared to expect the unexpected  and rapidly build on the results. Even small numbers can provide useful information to generate hypotheses, and dismissing these small numbers can result in important findings being missed.
The current effort to confirm and extend the modest efficacy observed in RV144 needs to be accelerated, but there is also a need to explore the efficacy of other candidate vaccines in parallel. Novel vaccine constructs also need to be tested in small experimental medicine trials to obtain early safety and immunogenicity data.
Lesson 4: there can be more than one way to develop effective vaccines
By 1962, a total of 400 million doses of the inactivated polio vaccine had been distributed in the United States . In the meantime, the development of a live-attenuated polio vaccine continued, championed by Albert Sabin . It was believed that an oral live-attenuated vaccine would induce a more solid and long-lasting protective immunity. The proof of the safety and effectiveness of the Sabin vaccine came from a massive trial conducted in 1959 in the former Soviet Union, involving some 11 million participants . These results provided the basis for the licensing of the Sabin vaccine in 1962.
In the case of HIV, one way to tackle the challenge is to envision a staged approach wherein the first generation of vaccines may provide limited efficacy. Adopting a product development ‘attitude’ earlier in the translational research effort, defining a critical path with intermediate milestones and go/no go decision points, would further accelerate the development of more effective vaccines .
Lesson 5: high expectations of current interventions could delay vaccine development
From 1916 onward, polio epidemics appeared in the United States each summer, with the most serious occurring in the 1940s and 1950s . There was an urgent need to develop preventive and therapeutic interventions. Some of the unsuccessful or impractical approaches used included nasal spray techniques to prevent transmission through the nasal mucosa, fly abatement campaigns to prevent fecal–oral transmission of polio, and even passive immunization . Overconfidence in these and other interventions might have created a distraction from the efforts, resources, and trial populations that could have accelerated vaccine development, but fortunately, the priority to develop a polio vaccine was always maintained.
Despite an exceptional medical and societal response to the HIV epidemic, more than 2 million people become infected with HIV every year, mostly in developing countries. Fortunately, the preventive potential of microbicides, preexposure prophylaxis, and earlier antiretroviral treatment of infected individuals has been demonstrated. All of these interventions, used in combination, may have a significant impact in reducing the incidence of HIV infections .
What is worrisome, however, is the misperception by some that we already have all the necessary tools to stop the AIDS epidemic, making a vaccine unnecessary. In fact, we need to continue expanding access to existing interventions while actively pursuing the development of a vaccine which, ultimately, like in the case of polio, will be the most cost-effective approach to stop HIV/AIDS, especially in the resource-limited populations.
Lesson 6: societal and political support is essential to sustain the vaccine development effort, with private foundations playing a critical role
The polio epidemic of 1952 was the worst in US history, causing nearly 58 000 paralytic cases, affecting all communities and causing widespread fear. Millions of Americans contributed financially to the polio vaccine development effort, which did not rely on government support, and the vaccine industry was fully engaged.
Having contracted the disease himself in 1921, Franklin Delano Roosevelt became a visible public champion of the crusade against polio. In 1938, President Roosevelt established the National Foundation for Infantile Paralysis, a private organization with the mission to lead, direct, and unify the fight against polio. Better known as the March of Dimes, the organization was led by Basil O’Connor, who was not a scientist, but rather a partner in Roosevelt's law firm. The March of Dimes advocated a mission-driven approach to polio research to complement the curiosity-driven approach then prevalent in the country.
In the United States, more than 500 000 people have already died of AIDS, and there are 1.2 million more currently living with HIV. Despite prevention efforts, the HIV incidence rate has held relatively stable, at approximately 50 000 new cases per year – mostly in marginalized populations . There is a reliance on government funding, whereas the pharmaceutical industry, primarily engaged in the most lucrative area of antiretroviral treatment, is only marginally involved in the development of preventive vaccines.
In general, HIV vaccine development has lacked the political support it needs, with one notable exception. On May 18, 1997, President Bill Clinton challenged the country to develop an HIV vaccine within 10 years . Most scientists were against promising a vaccine within a specific period of time, but others argued that having a goal would energize the field and convey the necessary sense of purpose and urgency. Sustainable political support over the long term is needed to build on President Clinton's 1997 challenge as well as on the 2009 results from RV144.
The largest share of HIV vaccine work is conducted and supported by US government agencies. Other important players, perhaps with more flexibility, include the International AIDS Vaccine Initiative, and the Bill & Melinda Gates Foundation, key partners of the Global HIV Vaccine Enterprise . In his 2012 annual letter, Bill Gates challenged the world to do more to develop an HIV vaccine. He argued that ‘plans for conducting trials of different constructs are still not as aggressive as they should be given how game changing a vaccine would be’.
How soon we will have an HIV vaccine depends upon the decisions we make today. The mission-driven approach that characterized the March of Dimes in their vaccine quest could be essential for success.
Lesson 7: appropriate funding is critical, but needs to be allocated strategically
By 1954, the March of Dimes had raised a total of US$296 million from the public, roughly equivalent to US$3.6 billion today. More than half of these funds went directly toward medical care, but 11% of the budget was reserved for their research program, mainly devoted to vaccines . The estimated budget for the 1-year field trial of the poliomyelitis vaccine was US$7.5 million, equivalent to US$91 million today.
The current annual global expenditure on the worldwide HIV/AIDS pandemic is around US$50–60 billion, with US$16.8 billion used in resource-limited countries. The total global annual investment on the development of a preventive HIV vaccine has been estimated at US$859 million .
Therefore, less than 2% of the total global investment on HIV/AIDS is going toward vaccine research. I suggest that now is the time to strategically increase funding with the specific goal of developing a practical vaccine within the next 10 years.
Lesson 8: it is important to prepare for success
Once the Salk vaccine was proven to be well tolerated and effective, Basil O’Connor's primary objective was to deliver it as quickly as possible in order to prevent the oncoming polio season. Sufficient vaccine was produced with anticipation of the trial results to immediately begin a comprehensive national immunization campaign.
Because the scientific community had very low expectations for the RV144 trial, the observed efficacy caught the field by surprise. Plans to confirm and extend the results of RV144 have been delayed by the need to manufacture new lots of candidate vaccines.
In the case of HIV, preparation for success would involve stronger engagement of the affected community, timely manufacturing of products, preparation of field sites for testing multiple vaccines, and appropriate regulatory discussions to expedite future use of a vaccine.
Drawing on lessons from the past, these views provide specific recommendations on how the polio vaccine trial could inform current efforts to develop an HIV vaccine.
If we have the humility and courage to apply some of these lessons, we may be able to accelerate the development of an HIV vaccine we so urgently need.
I thank Bruce Weniger for excellent suggestions and James Parr for assisting in the preparation of the article.
Conflicts of interest
There are no conflicts of interest.
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