The end of HIV?

Posted January 19th, 2016

No major viral epidemic has ever been brought under control without a vaccine.1

Introduction

Today, it would be hard to think of a greater public health achievement than the development of vaccines. Thanks to immunization, once-devastating diseases like smallpox, whooping cough, polio, measles and rubella are either extinct or nearly so. Millions of lives have been saved and an incalculable amount of human potential has survived and been realized.2

An HIV Vaccine?

Many argue that finding an HIV vaccine represents the best long-term hope for breaking the chain of HIV infection and ending AIDS.3 Vaccines remain the most efficient and effective way to eliminate an infectious disease because they are affordable and practical.3

Realistically, we know that HIV is an extremely difficult target for a vaccine. The virus has unique ways of evading the immune system, and the human body seems incapable of mounting an effective immune response against it.4 Nevertheless, right now many dedicated scientists around the world are working hard to develop a safe, effective HIV vaccine as rapidly as possible in order to prevent the continued growth of HIV infections.4

Why do we need a vaccine?

According to classic public health theory, controlling the spread of infectious diseases requires controlling the chain of infection. Strategies for preventing the spread of any disease focus on three interventions: (1) Controlling or eliminating the virus in the host; (2) preventing the agent from accessing a new host; (3) increasing the host's defenses (a.k.a., vaccination).5

We are using method 1 when we attempt to control HIV through the use of antiretroviral (ART) drugs. When successful, ART drugs can control the virus in the host to the extent that it cannot be transmitted to others. Similarly, we are using method 2 when we try to prevent HIV from accessing new hosts, by promoting condoms and clean needle programs.

PrEP?

One relatively recent approach is called Pre-exposure prophylaxis (PrEP).6 PrEP is considered to be a combination of the classic control and prevention strategies. With PrEP, HIV-negative individuals take anti-HIV medications before coming into contact with HIV to reduce their risk of becoming infected. The only drug currently approved for PrEP use is Truvada® (emtricitabine and tenofovir disoproxil fumarate). Taken as a once-daily oral pill, Truvada has been shown to prevent HIV from establishing infection inside the body.6 Newer types of preventive treatments are in the development pipeline that might reduce the required treatment frequency to injections only every three months.

Despite our efforts to control and prevent the spread of HIV, the problem remains that HIV treatment and prevention are failing far too often. The World Health Organization (WHO) estimates that in 2013, over 2 million people became newly infected globally.8

This leaves the third public health intervention, vaccination. Only vaccination offers the chance to break the chain of HIV infection without relying on fundamental changes in human behavior on a mass scale.9

The search

HIV vaccination studies have been active since 1987 – barely three years from when HIV was first identified as the cause of AIDS. Throughout the 1980’s, 1990’s and 2000’s, several candidate vaccines have progressed into human trials. One, VaxGen, made it to large-scale Phase III trials in 1998 but ultimately failed when promising animal studies could not be replicated in humans.10, 11

What's taking so long?

Unfortunately, the HIV virus comes in many varieties and can also escape detection by the immune system because it mutates rapidly. A similar process of mutation is why we need different vaccines with each new flu season, although the flu virus changes much more slowly than HIV.12

HIV is so effective at avoiding detection that, to date, no human has been proven to eliminate HIV using their own immune system.13 This in itself creates a barrier for HIV vaccine developers, since most vaccines come from replicating the immune response of a person who has successfully defeated an invading pathogen.13

Still, while these difficulties have slowed progress, perhaps a little perspective is in order. Creating a safe and effective vaccine is rarely a quick or simple process, as this chart shows:

Have we found the right path?

Until quite recently no HIV vaccine tested has shown any success in preventing infection. The most encouraging development has been the breakthrough confirmation that an HIV vaccine can actually reduce risk of infection.10

That proof of concept came in 2009, when a human trial in Thailand called RV144 released results. The trial showed that those who received the vaccine were 31 percent less likely to become infected than those who received a placebo.13 While a one-third protection rate is nowhere near good enough for general use, this was a significant milestone.

Successor vaccine designs based on the RV144 results are the subject of an intensive international research effort. One effort in particular is to redesign the vaccine in order to target the “clade C” subtype of HIV that is most common in Southern Africa.14

The African version of the vaccine began early trials in January of this year (2015). Based on these results, the next step would be large-scale human trials, perhaps in the 2016-2017 timeframe.13

In separate work, the US military has also been working to build on the RV144 results. Their goal is an improved version for use in Thailand, where the original vaccine was tested. It’s thought that this new design might enter human trials in 2018.13

Speaking on behalf of the Bill & Melinda Gates Foundation at a conference in January of 2015, Bill Gates raised hopes around the world when he remarked that the follow-on studies resulting from the RV144 trial offer the best chance to achieve an HIV vaccine within the next 15 years.14

Some observers found this to be an extremely optimistic view. But Gates’ point was that, while the RV144 trials were technically a failure, they have proven to be a rich resource of new knowledge and solid scientific ideas for subsequent vaccine designs.14

Going forward

Reflecting on the past 30 years of work developing an HIV vaccine, one researcher concludes that above all else, we clearly need “more shots on goal.”15 In other words, while HIV vaccine testing has been nearly constant since right after the disease was identified, in all that time we have only tested four unique vaccine concepts for clinical efficacy.15

By this line of reasoning, we should be working to accelerate trials for many different novel and promising HIV-1 vaccine candidates in order to generate more knowledge. In effect, this will give us more “shots” and better odds.15

Research funding

Of course, more research will cost more money. One question might be, are we spending enough?

Some argue that we are not. The Treatment Action Group (an HIV/AIDS advocacy group) observe that funding for the US National Institutes of Health (the world’s leading supporter of scientific research) has failed to keep pace with inflation in recent years.14

This graph shows the distribution and relative sizes of the vaccination R&D effort worldwide:

We can also look at spending another way. According to the Tufts Center for the Study of Drug Development, the total cost of developing a new prescription medicine that gains marketing approval is $2.6 billion – over the course of a decade.16 By comparison, spending for the HIV vaccine seems fairly robust at nearly $1 billion dollars per year. At present funding levels, HIV vaccine research would reach the $2.6 billion level in slightly over three years.

However, it could be argued that the Tufts study actually overstates the true cost of drug research by nearly half. Over $1.1 billion of the $2.6 billion amount is attributed to time costs. That is, these are the expected returns that investors forego while a drug is in development.16

But as the chart above makes clear, at only $31 million, industry investment represents only a tiny fraction of the amount being spent on vaccine research. The vast majority of research funding for an HIV vaccine comes from public and philanthropic sources.

If we exclude the time value of money for what are largely nonexistent investors, HIV vaccine research spending just in the United States ($584 million) will exceed the average cost of producing a new drug in only two years.

Funding questions aside, research continues and seems to be picking up speed. In all, nearly three dozen HIV vaccination trials are underway right now:

Conclusion

Vaccination is not the only path to defeat HIV and AIDS. Work continues to find a cure and especially to engage all HIV-positive persons with the care appropriate to their situation. Therapeutic vaccines, which work in people who are already infected, are also under investigation.

But a vaccine is still necessary. The Director of the National Institute of Allergy and Infectious Diseases (NIAID) recently wrote that while prevention and treatment with ART drugs have helped, we are still far from stopping the spread of HIV.9 While we should continue to make every effort to ramp-up ART delivery the only guarantee of an end to the AIDS pandemic is the combination of prevention methods and a safe and effective HIV vaccine.9

References
  1. amfAR. Progress in the Quest for an HIV Vaccine? May 19, 2005. Accessed at: http://www.amfar.org/Articles/In-The-Lab/Older/Progress-in-the-Quest-for-an-HIV-Vaccine--%28May-2005%29/ on 06.26.2015.
  2. Health Affairs. The History of Vaccines and Immunization: Familiar Patterns, New Challenges. May 2005 vol. 24 no. 3 611-621. Accessed at: http://content.healthaffairs.org/content/24/3/611.full on 06.23.2015.
  3. Fred Hutchinson Cancer Research Center. Why is an HIV vaccine needed? Accessed at: http://www.hvtn.org/en/science/hiv-vaccine-basics/why-hiv-vaccine.html on 06.09.2015.
  4. National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID). HIV Vaccine Research. Last Updated June 08, 2015. Accessed at: http://www.niaid.nih.gov/topics/hivaids/research/vaccines/Pages/default.aspx on 06.23.2015.
  5. Centers for Disease Control and Prevention. Principles of Epidemiology in Public Health Practice, Third Edition. An Introduction to Applied Epidemiology and Biostatistics Introduction to Epidemiology; Section 10: Chain of Infection. May 18, 2012. Accessed at: http://www.cdc.gov/ophss/csels/dsepd/ss1978/lesson1/section10.html on 06.24.2015.
  6. San Francisco AIDS Foundation. What is Pre-exposure Prophylaxis (PrEP)? Accessed at: http://men.prepfacts.org/the-basics/ on 11.20.2015.
  7. Aids.gov. The Global HIV/AIDS Epidemic . Nov. 13, 2014. Accessed at: https://www.aids.gov/hiv-aids-basics/hiv-aids-101/global-statistics/ on 06.24.2015.
  8. World Health Organization. Fact sheet: HIV/AIDS . Updated Nov. 2014. Accessed at: http://www.who.int/mediacentre/factsheets/fs360/en/ on 06.24.2015.
  9. The New England Journal of Medicine. Ending AIDS — Is an HIV Vaccine Necessary? Anthony S. Fauci, M.D., and Hilary D. Marston, M.D., M.P.H. Feb. 6, 2014. Accessed at: http://demystifyingmedicine.od.nih.gov/DM14/2014-02-11/NEJM-y2014v370p495.pdf on 07.07.2015.
  10. National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID). History of HIV Vaccine Research. May 21, 2013. Accessed at: http://www.niaid.nih.gov/topics/hivaids/research/vaccines/Pages/history.aspx on 06.25.2015.
  11. Business 2.0. End Of The Crusade VaxGen dreamed big and lost big when its AIDS vaccine failed a multimillion-dollar clinical trial. Oct. 1, 2003. Accessed at: http://money.cnn.com/magazines/business2/business2_archive/2003/10/01/349480/ on 07.07.2015.
  12. amfAR. Boosting Killer T cells to Eliminate HIV Reservoirs. Feb. 12, 2015. Accessed at: http://www.amfar.org/early-art-and-boosting-immuning/
  13. AVAC. AIDS Vaccines: An Introductory Factsheet. March, 2015. Accessed at: http://www.avac.org/sites/default/files/resource-files/AVAC_vaccine_factsheet_march2015.pdf on 06.29.2015.
  14. TAGline. An HIV Cure and a Vaccine within the Next 15 Years? Spring 2015. Accessed at: http://www.treatmentactiongroup.org/tagline/2015/spring/hiv-cure-and-vaccine-within-next-15-years on 07.02.2015.
  15. AVAC. AIDS Vaccines: An Introductory Factsheet. March, 2015. Accessed at: http://www.avac.org/sites/default/files/resource-files/AVAC_vaccine_factsheet_march2015.pdf on 06.29.2015.
  16. TAGline. An HIV Cure and a Vaccine within the Next 15 Years? Spring 2015. Accessed at: http://www.treatmentactiongroup.org/tagline/2015/spring/hiv-cure-and-vaccine-within-next-15-years on 07.02.2015.
  17. New England Journal of Medicine. The Quest for an HIV-1 Vaccine — Moving Forward. 2013; 369:2073-2076 November 28, 2013 DOI: 10.1056/NEJMp1312711. Accessed at: http://www.nejm.org/doi/full/10.1056/NEJMp1312711 on 07.07.2015.
  18. Tufts Center for the Study of Drug Development. Cost to Develop and Win Marketing Approval for a New Drug Is $2.6 Billion. Nov. 18, 2014. Accessed at: http://csdd.tufts.edu/news/complete_story/pr_tufts_csdd_2014_cost_study on 07.07.2015.