Immunisation protecting our children from disease
Box 4 | WHO's Global Programme for Vaccines and Immunization
This is a paper by Sir Gustav Nossal published in The Immunologist, 1997, 5/1. It is reproduced here with the permission of the author and the publisher.
Two hundred years after Edward Jenner's introduction of vaccination against smallpox, and 20 years after the total eradication of this dreadful scourge from the world, it is opportune to ask how true the world has been to the Jennerian legacy. Are all the world's children reaping the benefits of immunization, arguably history's most cost-effective public health tool? The answer must be probed at three levels:
- First, how are we doing at deploying the vaccines which, by universal agreement, all children require?
- Second, what plans exist to make newly discovered, important vaccines accessible in developing countries?
- Third, what is in the research pipeline, and how are we doing in respect of promoting and coordinating research?
Two years ago, the Director of the World Health Organization gave the author an awesome challenge. It was decided to amalgamate two previously existing programs, the Expanded Programme on Immunization and the Programme for Vaccine Development, together with a new effort into assurance of vaccine supply and quality, into one large all-embracing program termed the 'Global Programme for Vaccines and Immunization'. The strategic development of this program was to be scrutinized by SAGE (the Scientific Advisory Group of Experts), of which the author was made Chairman. Furthermore, there are players other than WHO in the world immunization scene, prominently including UNICEF, the World Bank, and a number of nongovernmental organizations and foundations. They had been knit into a loose confederation of interest termed the Children's Vaccine Initiative (CVI). It was decided that the SAGE should also oversee its activities.
To put the matter into perspective, the following statistics are of relevance:
- About 130 million children are born into the world each year, the great majority of them in developing countries.
- There are about 12 million deaths per year in children aged 1 week to 14 years.
- Approximately 9 million of these deaths are due to communicable diseases.
- While vaccination is surely preventing very many deaths, there remain about 3 million deaths per year from diseases where vaccines presently exist; the other 6 million deaths are due to diseases where either no vaccine exists or where full registration of the vaccine has not yet occurred.
In view of the above, there is clearly a huge challenge ahead for SAGE, but a good beginning has been made. Let us consider first the eight vaccines which are supposed to be universally deployed. These are diphtheria, pertussis, tetanus, poliomyelitis, measles, BCG for tuberculosis, hepatitis B, and yellow fever in countries where this disease is endemic. At the time of the smallpox eradication triumph, immunization rates were extremely low, but now about 80% of the world's children are being reached though it must be admitted that not all of these complete the full immunization schedule.
The most encouraging progress has been made in the case of poliomyelitis, where there is a very good chance of total eradication by the year 2000*. The industrialized countries have been essentially free of polio for quite a few years. Polio transmission has ceased in the Western hemisphere, and there has also been no case of natural polio in any American country over the past 5 years. Bearing in mind how poor some of these countries are, this is a great public health triumph and a tribute not only to WHO and UNICEF, but also to Rotary International through their Polio Plus Campaign, and to the health ministries of the Latin American countries. As a result of this success, many other countries have buckled down to the task of polio eradication, the chief tool being "National Immunization Days" to supplement regular infant immunization programs. On a National Immunization Day, all children under 5 years of age receive the oral poliomyelitis vaccine, regardless of their previous vaccination history. This is a very powerful tool in breaking transmission chains. Highly successful National Immunization Days have been held in China and India. It is hoped that the Western Pacific Region, including China, will be polio-free within a year or two, leaving India and particularly Subsaharan Africa as the remaining very major challenges.
The success of polio eradication in the Americas has posed an interesting problem for richer countries like the United States. Given that there is no more natural polio transmission, many feel that the very occasional (perhaps one in a million) reversion to virulence of the oral polio vaccine represents an unacceptable risk. United States citizens are therefore to be offered Salk-type inactivated polio vaccine as two injections prior to two further doses or oral polio vaccine (and in some instances even four inactivated polio vaccine shots). While this is more expensive than the oral vaccine, the cost differential is not a major factor in a rich country. The oral vaccine remains the favored tool in developing countries.
There has also been great progress in measles control, and again a significant number of Latin American countries appear to have achieved total eradication. Here, interestingly, the industrial world is lagging behind, although the United Kingdom has recently succeeded in essentially wiping out measles infection (although sporadic imported cases still occur). Many feel that measles, which still has a 2-3% mortality in developing countries, should be the next disease targeted for eradication once polio is gone.
Neonatal tetanus remains a big problem in countries where obstetric hygiene is defective. Here the task is to immunize pregnant women so that antibodies can cross the placenta and protect the infant. A tremendous help here would be "one-shot" vaccines because it is sometimes difficult to persuade women to return for booster injections.
Unfortunately, the BCG vaccine has proven to be not as good as was originally hoped. It does do a good job in protecting infants from tuberculous meningitis and miliary tuberculosis, but the protection is clearly not strong enough to safeguard against pulmonary tuberculosis in young adult life. A better vaccine is badly needed.
Hepatitis B is a recent addition to the list of vaccines in the WHO program. Although the costs have come down sharply since the first introduction of this excellent vaccine, they still remain an order of magnitude higher than the other vaccines on our list, so new resources are badly needed. One advantageous feature will be transfer of vaccine-producing technology to some of the larger developing countries, thereby solving hard currency problems.
The challenge of newly introduced vaccines
Beyond the eight vaccines discussed above, it will be imperative to make available to the developing countries some of the newer vaccines that have emerged from the research pipeline. One excellent example is Haemophilus influenzae B, or HIB, vaccine against meningitis. This sophisticated vaccine is a conjugate which appropriately stimulates T-cell-B-cell collaboration and has proven remarkably effective against the major cause of bacterial meningitis. In a recent trial in The Gambia, it has also proven effective against other forms of invasive HIB disease, such as HIB pneumonia. Once again, resources will have to be raised to enable this vaccine to be more widely delivered.
Similar conjugate vaccines should soon be available for meningococci and pneumococci. Within this category of emerging vaccines there are also new and much more effective vaccines against cholera, typhoid, and perhaps other diarrheal diseases such as bacillary dysentery. As yet, it is unclear whether funds will be available to deploy such vaccines throughout the countries that most need them. SAGE and WHO are working with industry in an attempt to introduce tiered pricing, with countries being divided into five bands according to their degree of affluence or poverty. It is felt that many countries will need only encouragement and persuasion, whereas others may need virtually the whole cost of the vaccines to be subsidized through the international aid system.
Vaccine research and development
Both academic laboratories and industry appear to have got a "second wind" with respect to vaccine research and development. As a result, there are exciting developments both with respect to diseases for which vaccines are being actively sought and with respect to new ideas about vaccine delivery. In the former category there are extremely difficult problems, such as malaria and HIB, but also more accessible developments, such as rotavirus diarrhea, respiratory syncytial virus, dengue, and new approaches to a tuberculosis vaccine. With regard to the latter area at least five new developments could be mentioned:
- A range of nontoxic adjuvant substances suitable for human use are undergoing advanced clinical trials.
- Microencapsulation techniques permitting "one-shot" vaccination are on the threshold of success.
- Vectored vaccines, where genes for the antigen of interest are engineered into a harmless virus or bacterium, are also in clinical trials.
- Mucosal immunization, where the vaccine is delivered orally or intranasally in combination with a mucosal adjuvant, are showing promise.
- Finally, and perhaps most excitingly, it has been shown that intramuscular or intradermal injection of nucleic acids can lead to immunization. This involves engineering suitable plasmids with the gene for an antigen or antigens of interest, preceded by a strong promoter. Amazingly, this manipulation can lead to both T-and B-cell immunity, despite clear evidence that the amount of antigen produced is very small. This is an extremely rapidly developing area of vaccine research.
Vaccine research is not confined to diseases that are chiefly of interest to the developing countries. Recently, an acellular pertussis vaccine has been introduced which seems to get around the problem of reactogenicity of current whole, killed bacterial pertussis vaccine. A great deal of research has gone into vaccines against the sexually transmitted disease herpes simplex type 2 virus, which causes genital herpes. Active research is promoting vaccines against those strains of the human papilloma virus that are associated with cervical cancer. Several strategies are being used to develop a Helicobacter pylori vaccine as a preventive of peptic ulceration and possibly gastric cancer. Anti-cancer promise is also present in vaccines against hepatitis B, hepatitis C, and Epstein-Barr virus. More distantly, exciting possibilities exist for anti-cancer vaccines using a variety of tumor-associated antigens.
The Global Programme for Vaccines and Immunization is not too likely to run out of work to do! That being said, it seems certain that within 20 years the situation with regard to communicable diseases globally will have improved very measurably. Prevention is not only better than cure it is also much cheaper. With the health expenditure globally being under very great strain, this is no trivial point.
* Update on the status of Polio and the future
Many advances have been made since the publication of this paper in 1997. For example, in 2011 only 650 cases of Polio were reported in the 3 remaining countries where it exists, namely Nigeria, Afghanistan and Pakistan. This is a great improvement on the 350 000 cases that were reported worldwide in 1988.
A major outstanding challenge for researchers is to develop vaccines against
HIV, TB and malaria, all of which require a T cell and an antibody
response. Two good reviews on the future of vaccination research are:
Rappuoli, R and Aderem, A. 2011. A 2020 vision for vaccines against HIV, tuberculosis and malaria. Nature. 473: 463-9, and
Rappuoli, R et al. 2011. Vaccines for the twenty-first century society. Nature Reviews Immunology. 11:865-72
The Science of Immunisation: Questions and Answers (Australian Academy of Science)
Update November 2012.