(May 2006) Despite advances in prevention and treatment, AIDS, tuberculosis (TB), and cervical cancer remain among the most serious and costly threats to world health. Effective vaccines against each of these diseases would drastically alter their global profile and save millions of lives annually as well as tens of millions of disability-adjusted life-years (DALYs) (see Table 1 for the estimated burden of each of these diseases).


Table 1
Estimated Burden of Disease From AIDS, TB, and Cervical Cancer, 2002-2005

AIDS
TB
Cervical Cancer
Annual deaths
3.1 million
1.7 million
274,000
DALYs lost
84 million
35 million
3.3 million

Note: Disability-adjusted life-year is a summary measure that includes the number of healthy years of life lost to premature death and the number of years spent with less than full health.
Sources: UNAIDS/WHO, AIDS Epidemic Update: December 2005 (2005); WHO, Global Tuberculosis Control—Surveillance, Planning, and Financing, WHO Report 2006 (2006); International Agency for Research on Cancer, Globocan 2002 Database (www-dep.iarc.fr); and WHO, Global Burden of Disease Estimates for 2002 (www.who.int).


Although vaccines have proven highly cost-effective and extremely successful in controlling other diseases—from measles to polio to smallpox—challenges continue to hamper progress toward vaccines for HIV, TB, and cervical cancer:

  • An HIV vaccine remains elusive because of the virus's rapid rate of mutation.
  • Although TB does have a vaccine on the market—Bacillus Calmette-Guerin (BCG), it primarily protects children from the most severe forms of TB and does not offer long-term immunity in adults. Other TB vaccines are only in the first phase of clinical testing.
  • Two vaccines for cervical cancer—Cervarix and Gardasil—are pending regulatory approval, but challenges (such as immunization of the target group, adolescent women) remain to vaccine introduction and use at the community level.1

Successful implementation of the cervical cancer vaccine could pave the way for introduction of a future HIV or TB vaccine, since a vaccine for HIV or TB would also be aimed at adolescents. Many of the lessons learned from cervical cancer vaccination efforts could potentially be applied to an HIV or TB vaccine.2

In the meantime, a host of other factors—including inadequate infrastructure for large-scale clinical trials and considerable costs of development and testing—are working against the vaccine effort. Increased investment and funding from a variety of sources will be necessary to meet these challenges and speed vaccine development and introduction.

Potential Impact of Future Vaccines

More than 40 million people are living with HIV. In 2005 alone, close to 5 million people were newly infected with the virus, and over 3 million died of AIDS.3 While effective prevention programs and improved AIDS treatments have slowed the spread of the epidemic, AIDS continues to take millions of lives.

The convergence of the HIV and TB epidemics has led to even more devastating effects, with each epidemic worsening the effects of the other. (For more information on the intersection of HIV and TB, see Intersecting Epidemics: Tuberculosis and HIV.) Almost 15 million people worldwide are infected with TB—some 9 million alone in 2004.4 Although TB is treatable, strains that are resistant to first-line TB drugs have emerged, and people living with HIV are at increased risk of developing these forms of multi-drug-resistant tuberculosis (MDR-TB). MDR-TB requires up to two years of treatment with more expensive second- and third-line drugs that are also more toxic.5


Table 2
Impact of a Future HIV Vaccine, 2015-2030

Vaccine efficacy
Population coverage
Averted infections (millions)
40%
20%
29
60%
30%
47
90%
40%
71

Source: IAVI, Estimating the Global Impact of an AIDS Vaccine: Policy Brief 8 (New York: IAVI, 2005).


As Table 2 shows, even partially effective HIV vaccines given to less than one-half the population in low- and middle-income countries would be likely to avert tens of millions of new HIV infections.6 And a new TB vaccine introduced between 2014 and 2018 could reduce TB incidence in Africa and Southeast Asia by 20 percent during the first 10 years and by 40 percent by the year 2050.7 But a vaccine for either HIV or TB remains at least a decade away.

By contrast, two vaccines to prevent the transmission of human papillomavirus (HPV)—a necessary but not sufficient cause of cervical cancer—are in the final stages of development. While improved screening and treatment options for HPV have been presented in developing countries (where 80 percent of the world's 500,000 annual cervical cancer cases occur), basic preventive measures such as Pap smears are still largely unavailable in these countries. An HPV vaccine would provide the protection needed to effectively reduce cervical cancer rates by two-thirds over several decades.8

Vaccine Development Process and Pipeline

Current vaccine candidates for HIV, TB, and HPV are in various stages of development (see Table 3). As candidates are tested at each stage of the process, only a small proportion make it through to the next stage.9 The vaccine development process is a lengthy one—starting from preclinical laboratory testing and animal studies, through three phases of human clinical trials, and finally to the licensing and approval stage:

  • In the preclinical stage, basic science research is conducted in a laboratory setting, often with cell or tissue cultures. If the initial results are promising, the vaccine candidates are tested in laboratory animals. Successful animal testing can lead to the next stage—human clinical trials.
  • Phase I of human clinical trials ensures the safety of the vaccine, involving only small groups of individuals.
  • Phase II determines both safety and immune response among hundreds of people who are similar in age and other characteristics to the target population.
  • Phase III establishes efficacy—whether the vaccine prevents the disease as intended—and is conducted among thousands of people from the target population at the community level.

Vaccine candidates that are successful in Phase III clinical trials may advance to the licensing and regulatory approval stage, where regulatory agencies review all documentation from the various stages of development to determine whether a product is safe and beneficial for the public. Given the need to establish both safety and efficacy, vaccine development can take at least 10 years and sometimes much longer.10


Table 3
Current Vaccine Candidates for HIV/AIDS, Tuberculosis, and Cervical Cancer

Preclinical
Phase I
Phase II
Phase III
HIV/AIDS
10
7
2
1
Tuberculosis
7
4
---
---
Cervical Cancer
6
1
---
2

Source: WHO, New Vaccines Against Infectious Diseases: Research and Development Status (2006).


A variety of TB candidates are being tested, all of which are in Phase I trials. Dozens of prospective vaccines for HIV have been tested, but only one is currently undergoing Phase III clinical trials. The vaccines for HPV have been the most successful to date: Two candidates, Cervarix and Gardasil, have gone through Phase III trials and are at the stage of regulatory approval.11

But the approval process itself can also be cumbersome and time-consuming. An application for the approval of Gardasil was submitted to the Food and Drug Administration in December 2005, with an expedited decision (reserved for medications that address unmet medical needs) expected in June. Even with an expedited decision, however, a licensed vaccine for developing countries would only be available by 2007 at the earliest.12

Challenges in Vaccine Research and Development

In addition to the normal rigors of testing and approval, researchers and developers of vaccines face a variety of obstacles—effective design, lack of infrastructure for testing and manufacturing, and financing. Each of these challenges has specific implications for the development and production of vaccines to combat HIV, TB, or cervical cancer.

Effective vaccine design. Designing a vaccine that elicits the appropriate immune response can be an arduous process. This is particularly true for the HIV vaccine because there are so many different strains of the virus. HIV is constantly mutating and changing, and each person living with HIV has a slightly different viral makeup.

Regionally, there is even greater viral diversity. Viruses in Africa are different from those in Asia. Additionally, an individual who is repeatedly exposed to HIV may be infected with two different strains of the virus, which then combine to form a new "recombinant" virus. Designing a vaccine that protects against the many different and constantly changing strains of the virus is an extremely difficult task.13

The prospects for designing a new vaccine for TB are more promising. The existence of the current BCG vaccine for children provides a good foundation for developing a new vaccine.14 Additionally, recent advances in understanding immune responses to tuberculosis infection have also enhanced development efforts. Nevertheless, a vaccine that provides consistent protection against TB may still prove difficult to develop. And while a future TB vaccine may protect the general population, it may not be as effective in areas with high levels of HIV coinfection.15

Having made it through the design process, HPV vaccines have been the most promising to date. However, these vaccines are still only effective against the two HPV strains that cause 70 percent of cervical cancer cases, leaving women who become infected with other strains still at risk of cervical cancer.16 Further research and development will be necessary in order to produce vaccines that block the other strains of HPV.

Lack of infrastructure for trials and manufacture. Vaccine developers must contend with the lack of infrastructure and facilities for conducting large-scale clinical trials in developing countries.17 In Phase III trials, the developer must not only manufacture the vaccine in the relatively small amounts needed for the trials, but must also be prepared to manufacture the vaccine for wider use as soon as possible in the event that the vaccine is found to be effective—requiring sufficient investment in manufacturing capacity. However, developers also face considerable risks by investing large amounts in manufacturing capacity before the trials conclude, since the vaccine may yet be proven ineffective.18

Cost of development. And given the many scientific and practical challenges involved in vaccine development, the process is extremely expensive. Pharmaceutical companies are reluctant to invest large sums of money into a vaccine unless they are assured a market to recover their costs. Thus, these companies lack the economic incentive to tackle vaccines for diseases that primarily plague developing counties—knowing that governments and the public will most likely be unable to afford the vaccines.19

The ongoing costs of developing an HIV vaccine are exceedingly high because of the virus' complexity. While $680 million were spent in 2004 alone on AIDS vaccine research and development, a funding gap still exists of approximately $350 million to $400 million per year.20

Recently renewed attention from the STOP TB Partnership and increased funding from the Bill & Melinda Gates Foundation are very encouraging, but current funding for a TB vaccine is still insufficient. In order to produce a vaccine by 2015, a total of $3.64 billion will be needed over the course of the next nine years—of which only $2.07 billion is available. The funding gap lies mainly in inadequate investment from the pharmaceutical industry.21

Further Hurdles and Promising Prospects

Even though the HPV vaccine has made it through the development process, obstacles persist as it is introduced and delivered to young people. Because HPV is a sexually transmitted infection, vaccination efforts need to be aimed at adolescent women before they become sexually active. Immunizing adolescents against an STI will not only be controversial, but also logistically difficult given the lack of infrastructure for reaching this age group.22

Despite all of the obstacles facing vaccines for HIV, TB, and cervical cancer, efforts are ongoing to bring vaccines on all three diseases to the table. Several global initiatives are working to accelerate vaccine development for HIV and TB and lay the groundwork for introducing an HPV vaccine. An in-depth discussion of challenges facing the introduction of HPV vaccines as well as prospects for increased funding and investment for all three vaccines will be covered in a PRB web article in June 2006.


Marya Khan is a research associate at the Population Reference Bureau.


References

  1. Cynthia Dailard, "The Public Health Promise and Potential Pitfalls of the World's First Cervical Cancer Vaccine," Guttmacher Policy Review 9, no. 1 (2006).
  2. International AIDS Vaccine Initiative, Vax: AIDS Vaccine Bulletin 4, no. 2 (New York: IAVI, 2006).
  3. Joint United Nations Programme on HIV/AIDS (UNAIDS)/World Health Organization (WHO), AIDS Epidemic Update: December 2005 (Geneva: UNAIDS/WHO, 2005).
  4. WHO, Global Tuberculosis Control—Surveillance, Planning, and Financing: WHO Report 2006 (Geneva: WHO, 2006).
  5. WHO, Tuberculosis: Fact Sheet No. 104, March 2006, accessed online at www.who.int, on March 23, 2006; and Heidi Worley, "Intersecting Epidemics: Tuberculosis and HIV" (April 2006), accessed online at www.prb.org.
  6. IAVI, Estimating the Global Impact of an AIDS Vaccine: Policy Brief 8 (New York: IAVI, 2005).
  7. STOP TB Partnership and WHO, Global Plan to Stop TB 2006-2015 (Geneva: WHO, 2006).
  8. International Agency for Research on Cancer, Globocan 2002 Database; Lori Ashford and Yvette Collymore, Preventing Cervical Cancer Worldwide (Washington, DC: Population Reference Bureau and Alliance for Cervical Cancer Prevention, 2004); and Dailard, "The Public Health Promise and Potential Pitfalls of the World's First Cervical Cancer Vaccine."
  9. WHO, Development of New Vaccines: Fact Sheet No. 289, April 2005, accessed online at www.who.int, on March 24, 2006; and IAVI, Understanding AIDS Vaccines: An Anthology of Primers from VAX, accessed online at www.iavi.org, on April 11, 2006.
  10. WHO, Development of New Vaccines; and IAVI, Understanding AIDS Vaccines.
  11. James Kaper, Rino Rappuoli, and Merry Buckley, Vaccine Development: Current Status and Future Needs (Washington, DC: American Society for Microbiology, 2005).
  12. Dailard, "The Public Health Promise and Potential Pitfalls of the World's First Cervical Cancer Vaccine."
  13. IAVI, Understanding AIDS Vaccines.
  14. Kaper, Rappuoli, and Buckley, Vaccine Development.
  15. STOP TB Partnership and WHO, Global Plan to Stop TB 2006-2015.
  16. Program for Appropriate Technology in Health (PATH), Introducing HPV Vaccines in Developing Countries: Overcoming the Challenges (2005), accessed online at www.path.org, on March 29, 2006.
  17. Kaper, Rappuoli, and Buckley, Vaccine Development.
  18. IAVI, Manufacturing an HIV Vaccine: Policy Issues and Options, Policy Brief 5 (2005), accessed online at www.iavi.org, on April 11, 2006.
  19. Kaper, Rappuoli, and Buckley, Vaccine Development.
  20. IAVI, Investing in AIDS Vaccines: Estimated Resources Required to Accelerate R&D (2005), accessed online at www.iavi.org, on April 11, 2006.
  21. STOP TB Partnership and WHO, Global Plan to Stop TB 2006-2015.
  22. Dailard, "The Public Health Promise and Potential Pitfalls of the World's First Cervical Cancer Vaccine."