Accelerating research and development

SETH F. BERKLEY

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HISTORY will not judge HIV/AIDS kindly. The human toll is expected to be the greatest of any infectious outbreak. Yet the harshest words will be reserved for how the world responded, or rather failed to respond, to the epidemic. In the face of potential unprecedented disaster, we have been unconscionably slow to deploy the tools at our disposal to thwart suffering and destruction. We have been even slower to commit resources to create new technologies that could decisively end our generation’s ‘great plague’. The world can and must do better.

The first AIDS case was identified in 1981, and HIV was unmasked as the culprit three years later. In the two decades since, we have learned how to fight back. We know that the spread of HIV can be greatly stemmed by promoting behaviours that interrupt its transmission. We also know that those who are infected can often extend their healthy years with the latest antiretroviral medicines. Yet, knowledge has not translated into action. The United Nations estimates that just a fraction of those who could benefit from antiretrovirals are able to afford them; in sub-Saharan Africa, a paltry 30,000 of the 30 million living with HIV get treatment.

With rare exception, programmes to educate people about how to protect themselves when having sex or using drugs are underfunded, if implemented at all, as well as stymied by widespread reluctance to discuss what are perceived as taboo subjects. Sexually active adults and adolescents need to be able to get quality, affordable condoms and be instructed in how to use them properly. Providing clean needles to injection drug users can make a significant dent in infections among this population, and often has the added benefit of leading substance abusers to counselling.

The world cannot waste any more time in expanding access to these life-saving and life-prolonging interventions. At the same time, it is imperative that we significantly step up research and development for even better treatment and prevention strategies.

Safer and more effective anti-retrovirals: Antiretroviral therapy has proven to be a dramatic medical advance. Not only are these medicines powerful ammunition against AIDS, they also represent one of the few classes of drugs ever to treat any viral infection. Still, there is no denying that current antiretrovirals are highly imperfect. In many people, the virus eventually finds a way around them; recent research estimates that many people infected with HIV are, or likely will become, resistant to every one of nearly 20 antiretroviral compounds. What is more, the medicines are very difficult for even the most diligent of users to take properly, requiring strict adherence to a daily schedule of multiple pills. Antiretrovirals often cause debilitating side effects as well. Safer, more effective and simpler anti-retroviral regimens are badly needed.

Topical creams to block HIV: Even when tried in earnest, promoting safer sex can go only so far in curbing HIV’s momentum. There are many groups of people for whom safer sex is not an option. For example, HIV infections are growing fast among young married women who are monogamous to their spouses. However, the husbands are not monogamous, and these women lack the social standing to demand that the men use condoms. Microbicides would offer a solution. Sometimes analogised as invisible condoms, microbicides would be colourless, odourless creams or gels applied topically to the genitalia to block HIV (and probably other sexually transmitted infections, which can wreak their own havoc as well as increase susceptibility to HIV). Unlike condoms, any one partner could use microbicides without having to rely on the other. Also, microbicides may be able to give women who want to get pregnant the option of doing so, while still guarding against disease.

 

 

A preventive AIDS vaccine: Preventive vaccines have been discovered for many other diseases – polio, smallpox, measles, yellow fever, hepatitis – eradicating or substantially taming these killers. It is long past due to add HIV/AIDS to the list. The ultimate pre-emptive strike, a vaccine would be given to people uninfected with HIV to shield them from the virus regardless of the mode of transmission, including during sex or through injected drug use or other direct contact with blood. Ideally, an AIDS vaccine would confer long-lasting protection in one or a few relatively cheap and unintrusive doses. Like microbicides, vaccination would have particular benefit for women and other socially disadvantaged groups for whom existing prevention methods fall short. In addition, a vaccine would protect people who do not want to admit, or do not know, that they need protection. It is estimated that 9 in 10 people who are living with HIV do not think that they are infected or are at risk of becoming so.

Rapid diagnostics: Although the test to detect infection with HIV is highly accurate, it has one major drawback – sending the sample for laboratory analysis can take days or weeks. Therefore, people seeking to know if they have contracted the virus must make two visits to a testing clinic. This has proven to be a major problem as a substantial proportion of people who get an HIV test never return to find out their results. We could eliminate this barrier by developing tests for HIV that yield results much more quickly. The same is true for tests to diagnose other sexually transmitted infections.

 

 

Vaccines, microbicides and better antiretrovirals – these are not pie-in-the-sky ideas, but real possibilities. Why then has their development been stunted? To be sure, there are many scientific challenges outstanding, as HIV is a wily invader that has demonstrated itself to be extraordinarily resilient to counterattack. Yet few in the field believe that the virus is invulnerable. Instead, progress is being held back just as much, and perhaps more so, by nontechnical barriers. Interest and money for research and development into new HIV/AIDS prevention and therapy are in terribly short supply, paling in comparison with the scope of the epidemic.

The organisation I lead, the nonprofit International AIDS Vaccine Initiative (IAVI; www.iavi.org), is working to overcome the economic and political obstacles impeding research and development of vaccines to prevent HIV/AIDS. Our programmes are focused exclusively on vaccines, but they are a model to be duplicated for other products and other diseases. Similar groups like the Alliance for Microbicide Development and the Malaria Vaccine Initiative are doing just this.

There are four hallmarks of IAVI’s work to speed the search for an AIDS vaccine: (i) Innovative incentives to encourage investment; (ii) Cross-national collaboration; (iii) High-level political advocacy; and (iv) Advance planning for access.

 

 

Innovative incentives to encourage investment: Economists use the term ‘market failure’ to describe a situation in which a commodity is in high demand, but because those who need it most are least able to pay, there is little incentive for investment in its discovery and production. This characterises AIDS vaccines precisely. A vaccine that could stop the virus would yield untold benefit. However, the HIV burden is highly concentrated in developing countries, where per capita annual spending on all health programmes typically amounts to US$10 or less. Indeed, leading companies have been significantly deterred from pursuing AIDS vaccines, because a successful vaccine that would be sold primarily to developing countries (or to donor agencies that would supply developing countries) promises little potential as a money maker.

Nearly a generation after HIV was identified as the cause of AIDS, only a handful of investigational vaccines have been constructed, and none has yet completed human trials to test whether it works. Small AIDS vaccine research outfits that must convince outside investors to finance their work, face an uphill battle raising capital. Large pharmaceutical firms already have resources that could be committed to AIDS vaccines, but they are accountable to shareholders who direct the management to pursue projects certain to return the most profit.

Fortunately, economists have a prescription for solving market failures: the public sector can provide incentives to encourage involvement in AIDS vaccine science. IAVI is pioneering this approach. We take money donated from governments and foundations worldwide and use it to finance and manage research partnerships to develop and test AIDS vaccines, with a focus on vaccines that are specifically designed for use in the developing world – for example, that are built from relatively inexpensive technology or that can be transported and stored in tropical climates without refrigeration. In the process, good ideas that otherwise would languish in the laboratory for want of support are fast-tracked to large-scale study.

 

 

As of the end of 2002, six novel AIDS vaccine candidates are in development with IAVI backing. This includes one vaccine being built by a team of researchers from a U.S. firm, Therion Biologics Corporation, and the Indian government. IAVI has negotiated an agreement whereby Therion will pioneer the procedure for manufacturing the vaccine and then transfer it to a firm in India (yet to be determined) for supplying doses for trials. Should the vaccine ultimately prove effective, the Indian firm would also have the rights to manufacture the product to sell to the worldwide market at low prices.

The Indian vaccine candidate, which should be ready to start human testing in late 2003 or early 2004, is tailored to a strain of HIV common in the country. This is significant because the genetic makeup of the virus prevalent in India, named sub-type C, is different from that in other regions. As we do not know whether geography-specific AIDS vaccines will be needed, it is critical that vaccines are developed for and tested in a variety of areas. The other candidates that IAVI is sponsoring are tailored for HIV strains common elsewhere in Asia, as well as throughout Africa.

It should be noted that IAVI does not receive any money from the new Global Fund to Fight AIDS, Tuberculosis and Malaria. The fund, which so far has raised US$ 2 billion, is not provisioned to pay for research and development for vaccines or any new prevention or treatment options. This is because the fund’s resources are inadequate even to cover its primary mandate to expand access to existing interventions. As donors continue to make contributions to the Global Fund, they should separately increase their support for research and development.

 

 

Cross-national collaboration: Developing and testing an AIDS vaccine requires extraordinary coordination of a diverse range of players. The researchers who conceive of a vaccine candidate are different from those who figure out how to manufacture it, from those who test the vaccine among thousands of volunteers over multiple years, and from those whose speciality is submitting a vaccine to government regulators for approval as safe and effective. All of these people are rarely found under one roof.

In financing and managing its AIDS vaccine research partnerships, IAVI joins experts from each of these disciplines, often forming teams that never before have worked together. We reach across national and regional boundaries, linking industrialised and developing countries. For example, IAVI is supporting an AIDS vaccine candidate developed by the University of Oxford in the U.K. and the University of Nairobi in Kenya and manufactured by companies in the U.K. and Germany. Human trials are underway at the Oxford and Nairobi campuses and they are scheduled to begin soon in Entebbe under the direction of the Ugandan government.

IAVI believes human trials of AIDS vaccines must be conducted transparently, with local communities meaningfully engaged. This is of particular importance in countries, such as India, where there is an unfortunate history of questionable practices in trials of other products. IAVI’s upcoming AIDS vaccine trial in India will be overseen first by the government, which must approve all aspects of the scientific programme, and second by a 30-member Community Advisory Board. Both of these safeguards are to assure that the strictest international standards are followed, including that trial volunteers must be truly volunteers, participating of their own free will and with the option to discontinue participation at any time. In addition, IAVI contracts with communications professionals throughout India to help provide information about AIDS vaccine trials and counter misinformation. One key point is that the vaccine tested does not contain any whole HIV, and therefore cannot cause infection or AIDS.

 

 

High-level political advocacy: Every December, the United Nations releases an update on the scope of the global HIV/AIDS epidemic. Last year, another five million men, women and children were infected with HIV, bringing the total of those living with the virus to 40 million. This translates into a rate of 15,000 new infections every day, or 600 each hour. At least as many new infections are projected for this year, and no corner of the globe is unaffected. Although HIV was relatively late to arrive in Asia, a catastrophe is brewing. In India, the number of people believed to be living with HIV, four million, is second only to South Africa.

As staggering as these numbers are, many people, particularly those in positions of leadership and power, still fail to fully grasp their significance and respond with decisive action. In some cases it is politically expedient to look the other way. The effect is to cripple AIDS vaccine research and development, as well as all programmes working to prevent and treat HIV.

There are important exceptions, however. In 1998, India’s Prime Minister, Atal Bihari Vajpayee, declared that finding an AIDS vaccine was a national goal, and to this end pledged to mobilise resources in ‘mission mode’. At a parliamentarian’s conference on HIV/AIDS in Delhi this spring, co-organised by IAVI, the prime minister reiterated his promise, standing in solidarity with leaders of the opposition party. Political will from the very top makes a real difference, and we must encourage others to follow suit, and then hold them accountable to deliver.

 

 

Advance planning for access: Once an effective AIDS vaccine is developed, it will need to be quickly distributed to all. This sounds obvious, yet history is not on the side of swift global access to new medical products – look no further than the abysmal record in getting antiretroviral medicines out to all living with HIV. Furthermore, no vaccine for any disease has ever been introduced simultaneously in the industrialised and developing worlds. Instead, developing countries wait an average of 20 years after new vaccines are licensed in industrialised nations. Business as usual has to change.

The key is planning now, before having discovered a vaccine. For example, the initial price of an AIDS vaccine is likely to be beyond the means of most developing countries. Today we can begin to mobilise political support to price vaccines by the ability to pay, and secure donor resources to purchase vaccines for poor countries. Similarly, it takes four to five years to build a vaccine plant, and if an AIDS vaccine were available tomorrow, it could not be made quickly and in sufficient quantity. We can mitigate delay by forging public-private partnerships to share the risk of building manufacturing capacity in advance of a licensed vaccine. Another challenge is that an AIDS vaccine will be targeted at adolescents and high-risk adults, yet the infrastructure for reaching these groups is inadequate. We should start establishing innovative systems for delivering AIDS vaccines to these populations.

 

 

Guaranteeing the speedy availability of future AIDS vaccines is nothing less than a complete paradigm shift, requiring radical changes in the way the world approaches nearly every aspect of deploying immunization. It also means a radical change in the way we think about scientific progress: We must not ‘consider a biomedical option as being scientifically effective until we have guaranteed its use by those who most need it,’ says Dr. Geeta Rao Gupta, President of the International Center for Research on Women and a member of IAVI’s Board of Directors.

Certainly, all of this is a tall order. And it is to say little of the raw scientific challenge of building a vaccine, which is formidable, but our ingenuity has persevered against other, similarly insidious diseases. For HIV, I firmly believe that if the world mobilises the concerted, well-funded effort that the epidemic demands, we will find a vaccine and microbicides and better antiretrovirals. And in turn, the end of AIDS for all time.

We have no time to lose. Every day sooner we find an AIDS vaccine, millions of lives can be saved.

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