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Of the 80-plus known infectious agents pathogenic for humans, there are now more than 30 vaccines against 26 mainly viral and bacterial infections and these greatly minimize subsequent disease and prevent death after exposure to those agents. This article describes the nature of the vaccines, from live attenuated agents to subunits, their efficacy and safety, and the kind of the immune responses generated by those vaccines, which are so effective. To date, all licensed vaccines generate especially specific antibodies, which attach to the infectious agent and therefore can very largely prevent infection. These vaccines have been so effective in developed countries in preventing mortality after a subsequent infection that attempts are being made to develop vaccines against many of the remaining infectious agents. Many of the latter are difficult to manipulate; they can cause persisting infections or show great antigenic variation. A range of new approaches to improve selected immune responses, such as immunization with DNA or chimeric live vectors, viral or bacterial, are under intense scrutiny, as well as genomic analysis of the agent.

Viral and bacterial vaccines, especially for childhood use, are one of the most successful public health measures of the last two centuries and have a good safety record. However, there are still many diseases that are caused by infectious agents for which vaccines are not available. Our increasing ability to manipulate the immune system offers hope that, in the future, at least some of these infections may be prevented by vaccination. A surprising recent development is the use of vaccine technology to test whether a range of other generally non-communicable diseases can be prevented (or at least controlled) in this way. Investigation of these diseases is still mainly at the experimental level, however the list includes different types of cancers, allergies, drug addiction and neurodegenerative diseases.

Few advances in the history of vaccination have had as quick a passage (approximately 10 years) from their discovery to clinical trials and, hopefully soon, registration as DNA immunisation. A very clear picture has now emerged of the recognition of the CpG-motif rich, chimaeric bacterial DNA by dendritic cells (antigen-presenting cells [APCs]) and the subsequent activation of T lymphocytes. Both humoral and comprehensive cell-mediated responses occur in both mice and primates. No significant safety concerns have been observed following administration to several hundred human volunteers, including some children. Of special interest is the generation of strong and high avidity CD8+ cytotoxic T lymphocyte (CTL) responses in primates, following priming with chimaeric DNA and subsequent boosting with a chimaeric live viral vector, such as an attenuated poxvirus or adenovirus. The DNA may also be used as a highly potent adjuvant, inducing mainly T helper (Th)1 responses. Advantages include its potential use in the presence of antibody to the targeted infectious agent and a generally simple manufacturing process.

Top of pageAbstract Compared with the earlier incidence of acute infectious diseases, the introduction of vaccines has been one of the major public health success achievements. In contrast, vaccine development to control some persisting infections such as HIV remains a major challenge. There are many similarities with this task and that of controlling tumours by immunotherapy. Generating CTL responses by using pulsed dendritic cells has become a popular approach and has led to success with the mouse model. With viral antigens, priming with DNA plasmids and boosting with a chimeric live vector results in high levels of CTL activity, and is worth trying with cancer. A recent review highlights three other difficulties posed by tumours: epitope stability, maiming or killing of CTL by the tumour, and accessibility of the tumour vasculature to immune components. The new ability to label CTL by staining with specific tetrameric peptide/MHC complexes offers the possibility of effectively studying this third aspect. Our increased knowledge of tumour-associated antigens, viral or otherwise, and our growing ability to manipulate the immune system, offers hope that control of at least some human tumours may be within reach. Keywords: cytotoxic T lymphocytes, chimeric vectors, dendritic cells, DNA, immunotherapy, neoplasia, tumour antigens, vaccination

In honor of the fiftieth anniversary of Frank MacFarlane Burnet's presentation of the clonal selection theory, two of his former staff reminisce about their interactions with this Nobel prize-winning scientist.

A safe vaccine to halt or slow the global HIV pandemic is urgently needed, yet the immediate prospects for an effective vaccine are poor. Experimental work to date suggests that live attenuated vaccines are most effective, but they raise serious safety concerns. The search for alternatives continues.

Early work on the roles of cytotoxic T lymphocytes (CTLs) in acute viral infections in animal models showed that i) the clearance of virus coincided with the increase in CTL activity rather than specific antibody levels, ii) transfer of CTLs after infection could protect from a lethal dose of virus, and iii) in primed, compared to naive, animals, CTL activity appeared 1-3 days earlier after a challenge infection. There is now a series of findings with individuals who have been exposed to HIV but are HIV-seronegative that suggest a protective role for CTLs. Usually after in vitro culture, HIV-specific CTLs have been isolated from i) infants born of infected mothers, ii) long-time partners of HIV-infected people, iii) some prostitutes in Africa, and iv). Most recently, 7/20 seronegative health care workers exposed once to HIV have been shown to possess HIV env-specific CTLs. The findings suggest that CTLs (a type I T cell response) may rapidly clear a low dose of HIV. Experiments with SIV are proposed that may provide more direct supporting data for this possibility.

The ideal vaccine is discussed under three headings. 1. The major requirements of the vaccine. This includes primarlly safety and efficacy and a number of other desirable features if the vaccine is to control a disease of global importance. These include cost, easy administration (e.g. orally), thermal stability, multivalency and long-lived immunlty 2. The nature and persistence of the immune responses which, as judged by model systems, are probably generated by the most effective viral vaccines in current human usage. 3. Approaches for developing future 'simplified" vaccines with similar levels of safety and efficacy so that these objectives are achieved.

There are three types of vaccines in medical use today—live, attenuated agents, mainly viruses; inactivated whole organisms; and subunit preparations. Though there are examples in each category of successful preparations, live attenuated viruses have almost invariably given long-lasting immunity after one or two administrations. Contributing reasons for this are gleaned, not from human vaccine studies, but from model systems and it is concluded that a vaccine needs to achieve four goals: activation of antigen-presenting cells; overcoming genetic variability in T cell responses; generation of high levels of T and B memory cells; and persistence of antigen for recruitment of B memory cells. Of the newer approaches to vaccine development, synthetic peptides have substantial limitations but should be successful in some cases. Subunit preparations may also be limited as a general method. Some live viral or bacterial vaccines, used as vectors of nucleic acid coding for other antigens, hold considerable promise as is illustrated by recent examples.

The enunciation and impact of Macfarlane Burnet's clonal selection theory of acquired immunity

Most vaccines are designed as a prophylactic measure, that is, to stimulate the immune response so that on subsequent exposure to the particular infectious agent, the extent of infection in the vaccinated individual is so low that disease does not occur. There is also increasing interest in designing vaccines that may be effective as a therapeutic measure. There are two contrasting types of infectious processes.

More than 70 bacteria, viruses, parasites, and fungi are serious human pathogens.1 Vaccines are available against some of these agents and are being developed against almost all the other bacteria and viruses and about half of the parasites. Table 1 lists infections for which there are now licensed vaccines and those for which a candidate vaccine has undergone a phase 3 clinical trial,2 indicating that a vaccine will probably be licensed within 5 to 10 years. Traditionally, attenuated vaccines were made by repeated passaging of the infectious agent in tissue culture or animal hosts until its virulence was greatly decreased but its . . .

It may be said that HIV vaccine issues could be divided into medical/scientific and sociopolitical/economic arenas. For the former the definition of efficacy and HIV antigenic variation are discussed while the role of the World Health Organization economic factors and accessibility are discussed for the latter. Simply put problems in both areas need to be solved. Unless an effective vaccine is rapidly developed and disseminated the world may be expect another 30 million people to become infected with HIV by the end of the decade. Involved parties must therefore move rapidly and responsibly to implement human efficacy trials. Of 3 potentially viable vaccine strategies only 2 have been submitted to such trials; whole inactivated HIV has not. The conducting of human vaccine trials furthered the development of strategies against smallpox rabies and polio. Similar professionalism and courage needs to be taken in developing a vaccine against HIV.

The prospects for many children born in developing countries to reach adulthood has been transformed over the last 30 years by the activities of the Expanded Programme of Immunization (EPI) established by the World Health Organization (WHO) in 1974. By 1990, about 80% of children had been vaccinated against six common childhood diseases. The advent of new technologies provided a strong stimulus to those involved in vaccine design, development and delivery, and offered the possibility of improving current vaccines, developing new vaccines and simplifying vaccination practices. This in turn led to the formation of the Children's Vaccine Initiative (CVI) in the early 1990s. The worldwide emergence of new diseases such as HIV/AIDS and the re-emergence of old diseases such as tuberculosis and cholera present additional challenges.

Twenty years ago, the terms 'altered self' and 'H-2 restriction', later modified to 'MHC-restriction', were coined to describe the finding by Peter Doherty and Rolf Zinkernagel that murine cytotoxic T cells (CTL) would lyse virus-infected target cells only if effector and target cells were H-2 compatible. This short review recalls those heady days and briefly recounts some of the later findings in three aspects of particular interest raised by the original finding: the nature of the T cell receptor, the composition and structure of the ligand on the target cell recognized by the TCR and the importance of CTL in the control and clearance of infections in general.

The efficacy of vaccines for prophylactic use is a function of the immune response elicited by activated lymphocytes. Based on the current understanding of these responses, their induction, and the most effective ways to obtain long-lived immunity, a novel protocol for the vaccination of children against seven childhood diseases, involving only two visits for vaccine administration, is proposed.

We have vaccines for nearly thirty of the more than seventy infectious diseases which are pathogenic for humans. Most of the vaccines, especially those to prevent childhood diseases, are highly effective with a high safety profile. Vaccines are being developed against many of the other bacteria and viruses, and some parasites. Occasionally, a new vaccine has to be withdrawn because of unexpected side effects. Smallpox remains the only infectious disease to have been eradicated. The Global Program to eradicate poliomyelitis initiated in 1988, has unfortunately run into difficulties. A few children immunised with the Sabin oral vaccine fail to clear the virus which can mutate over some years into a pathogenic form and spread rapidly unless large vaccination programs are re-introduced. Of major concern are emerging and re-emerging infectious diseases, especially HIV, for which there is currently no vaccine. Fortunately, new techniques are becoming available making it possible to consider developing vaccines based on inducing strong cell-mediated immune responses to control the agent's replication when antigenic variation in surface antigens (e.g. HIV, influenza) makes classical techniques based on induction of antibody responses less attractive.

In the first chapter, outbreaks of Ebola virus infections mainly in Africa are described as an example of an emerging disease, the sort of situation that will continue to face mankind as the human population goes on expanding. Although highly lethal, the virus is not highly infectious and is much less of a threat than HIV/AIDS. The remaining nine chapters mainly describe the work of different investigators who have made significant contributions to our current understanding of immunology: Elie Metchnikoff and phagocytes; Howard Florey and Alexander Fleming with penicillin; Jim Gowans and lymphocyte trafficking; Peter Medawar and Macfarlane Burnet on tolerance and clonal selection; Ivan Roitt and Ian Mackay on the discovery and control of autoimmune diseases; Jacques Miller and Robert Good and the role of the thymus; George Snell, Peter Gorer and Peter Doherty on the discovery and function of the MHC antigens; Kevin Lafferty on transplantation and the Summerlin affair at the Sloan- Kettering Institute; and Hugh McDevitt on Ir genes and the unresolved saga of suppressor effects in immune responses.

"Improbability of effective vaccination against human immunodeficiency virus ...", declares the title of a new paper by Dr Albert Sabin. But three immunologists see flaws in his argument.