The lack of a vaccine against certain infectious agents may not be because the scientific knowledge of the pathogen or the host is inadequate, but because it would not be cost-effective to develop one. At first sight, this may seem surprising, given that most vaccines are generally very cheap and effective. The Global Alliance for Vaccines and Immunisations (GAVI, a consortium of international health agencies, charities, governments and pharmaceutical companies formed in 1999) supplies the DTP vaccine against diphtheria, tetanus and pertussis (whooping cough), the oral polio vaccine, the combined MMR measles, mumps and rubella vaccine, and the BCG vaccine against tuberculosis, to immunise children in developing countries at a cost of under US$1 per dose. In addition, there is the cost of organising, conducting and evaluating a mass vaccination programme. Nevertheless, the cost per person for the most widely used vaccines is small – particularly when set against the estimated two million children who still die each year from vaccine-preventable diseases.
However, not all vaccines are cheap: some are priced above the means of the countries that need them most and supplies may not be sufficient to meet demand. For example, 12 million doses of a vaccine against all four of the major strains of meningococcal bacteria are sold to rich countries every year at differential prices, ranging up to US$50 a dose in the USA. An offer by the manufacturers to supply 2 million doses to African countries at $2.75 each was more than they could afford and far below the 10 million doses required (Lancet Infectious Diseases Newsdesk, 2002).
The major expense comes in the initial stages of laboratory research to develop a new vaccine, and particularly in conducting the clinical trials required to establish whether it is safe and effective (Box 1). This cost may be over US$150 million when all expenses are included. Commercial companies take strategic decisions as to whether such investment can be justified in relation to the returns available. The urgent work to develop HIV vaccines has been driven partly by the fact that an estimated 1.5 million people in the USA and Western Europe were living with HIV infection by the end of 2001, causing over 27 000 deaths annually. (Global and regional HIV/AIDS data are regularly updated on the WHO websites.) Given that over 90 per cent of AIDS deaths occur in poor countries, the extent to which HIV affects the rich countries of the world, where citizens would pay a lot for a protective vaccine, has been a factor in the race to develop the first one. But the world market of 6 billion people (since everyone is at risk from HIV) is the greatest possible incentive to investors, and hundreds of millions of dollars have been committed to research into protective and therapeutic HIV vaccines. (For reports on progress, see links to the International AIDS Vaccine Initiative website under Course Resources.)
Box 1 Clinical trials of vaccines
After extensive laboratory tests on animals, clinical trials of vaccine efficacy and safety take place in humans in three phases. Phase 1 trials assess the tolerability of the vaccine in a small number of healthy volunteers. Phase 2 trials test various vaccination regimens (dosage, spacing) for efficacy and tolerability in well-defined groups of a few hundred individuals who are at high risk of infection (e.g. in the case of HIV vaccine trials, the recipients have included injecting-drug users and sex workers). Effects of the vaccine on their immune responses are evaluated and the subsequent rate of infection in the vaccinees is compared with that in control groups who received placebo (dummy) vaccinations, or the existing vaccine where the trial is of a newer preparation. Phase 2 trials of therapeutic vaccines may also be conducted on already-infected subjects, to see if the vaccine slows the progression of the disease or has adverse effects (e.g. promoting a damaging inflammatory response). Phase 3 trials involve large groups of uninfected people (usually thousands) and may have a ‘multi-centre’ design, with different research teams evaluating the outcomes in different locations (see Figure 11). During the Phase 3 trials, attempts will be made to get the vaccine registered for use in the countries in which the first vaccination programme is to be launched. Thereafter, the performance of the vaccine is monitored in mass vaccination programmes in the target populations.
The prospect of lucrative markets in high-income countries has undoubtedly driven research into protective vaccines against human papilloma virus infection, a major contributory factor in cervical cancers, and into the development of a therapeutic vaccine that directs the immune system to destroy the ‘plaques and tangles’ in the brains of people with Alzheimer's disease. By comparison, resources for developing vaccines against parasite-mediated diseases, such as Chagas’ disease and sleeping sickness, which only affect poorer countries, have been comparatively meagre. In some cases the veterinary significance of a zoonotic pathogen or parasite may be given higher priority and this can initiate research into a vaccine that translates subsequently into a preparation for human usage.
Governments, charities and non-commercial organisations also take decisions on the relative merits of vaccines compared with other, more cost-effective, control measures. For example, syphilis is readily treated by antibiotics and the spirochaete has not become antibiotic resistant. Since most antibiotics are also cheap and even easier to administer than vaccines, there have been few incentives to develop a vaccine against syphilis. A similar argument has applied to many other bacterial diseases, such as streptococcal infections and gonorrhoea. However, with the increase in antibiotic resistance in many important bacterial pathogens, the balance of the argument is now shifting towards vaccine development.
For some infectious diseases – particularly the diarrhoeal diseases and those caused by parasites – public health strategies may be as (or more) effective than vaccination. For example, the provision of clean drinking water and sanitation has done more to prevent epidemics of cholera than has any vaccination programme.