VACCINES

What are vaccines?

Vaccines are substances injected into the body in order to produce an immune response. Usually, the substance is a bacterium or virus (or some component of one) that has been made harmless, and the objective is to produce a protective immunity in the individual. Later exposure to the full infectious organism then does not result in disease. Examples of infectious diseases commonly prevented by vaccination include tetanus and diphtheria, polio and hepatitis B.

Recently, therapeutic vaccines have come under development, especially for use in cancer. By priming the immune system to respond to an antigen (a substance that stimulates an immune response) that otherwise does not trigger it sufficiently, or at all, such as an antigen on the surface of a tumour, the immune system can be helped to destroy cancer cells. Such an approach might also be used to treat some infectious and other diseases.

Vaccination for disease prevention goes back almost 300 years in the UK, to inoculation to protect against smallpox, and builds upon the insights of pioneers such as Jenner, Pasteur and Robert Koch. The contribution of the pharmaceutical industry has been immense in developing vaccines with high levels of protective efficacy, improved storage stability and few side-effects. They are now manufactured on a scale that makes it possible to protect entire populations against diseases that were feared by earlier generations. Over the past twenty years, biotechnology has made an important contribution to this process, so that highly effective vaccines can be made without handling dangerous pathogens (organisms that cause disease). Such vaccines are often also better tolerated than the older vaccines that contained whole infectious organisms.

Who are vaccines recommended for?

Vaccination is used to prevent epidemics and to protect susceptible individuals against the risk of serious infectious diseases, especially where no treatment is available. It is especially appropriate for three main groups:

• children, to prevent childhood infections with potentially severe complications
• healthy adults travelling to areas of high prevalence of diseases such as hepatitis or typhoid fever
• at risk adults, such as the elderly or those taking immuno suppressive medication, who may suffer serious consequences from a disease that would not normally be severe in others.

In some instances, vaccination may be effective even when given after exposure to the organism that caused it. This is the case for rabies and tetanus, for example. Passive immunisation through injection of a specific antibody may be used to give short-term protection against an expected threat of infection, but such protection only lasts for a few weeks, until the antibody is cleared from the system. Vaccination is required for long-term immunity.

Vaccines are available for a variety of bacterial diseases, including cholera, diphtheria, typhoid fever, tetanus, tuberculosis, whooping cough (pertussis), pneumococcal pneumonia and bacterial meningitis. Vaccine-preventable viral diseases include hepatitis (A and B), measles, mumps, German measles (rubella), polio, rabies, influenza, tick-borne encephalitis, rotavirus, chickenpox and yellow fever.

In the UK, it is recommended that infants should be vaccinated at the age of two to four months against diphtheria, tetanus and pertussis (DTP), Haemophilus influenzae b (Hib), polio and type C meningococcal meningitis. This is normally followed at 12-15 months by vaccination against measles, mumps and rubella (MMR), with booster vaccinations for DTP and polio and MMR at three to five years. Vaccines are normally given by injection and combination products, such as DTP-Polio (Infanrix-IPV, GlaxoSmithKline and Repevax, Sanofi Pasteur MSD), have been developed to enable simultaneous vaccination against several diseases with the minimum number of injections.

Take-up of vaccinations is high, with 94 per cent of children immunised against DTP, Hib and polio, 93 per cent against meningitis C and 84 per cent against MMR by their second birthday, according to NHS statistics for England for 2005/06. The effectiveness of vaccination is shown by figures for the meningitis C programme, in which vaccine was given to those aged 15-17 as well as to infants in their first year, which show a 90 per cent drop in the number of cases of this potentially fatal disease in the targeted groups. Take-up of MMR fell following allegations of a link with autism in 1998, but has since begun to recover.

In adult life, vaccines are usually given to protect people travelling to less developed countries. Vaccines against hepatitis A, typhoid and yellow fever are commonly given for this purpose. However, the vaccine for hepatitis A must be given as two doses at an interval of 6-12 months and many people, realising the need for vaccination only a short while before travelling, do not return for the second injection, limiting the effectiveness of protection. Hepatitis B is another disease in which vaccines are of value, but the UK, unlike many other countries, does not include hepatitis B in the vaccination schedule for infants. Thus, when they reach sexual maturity, many young adults are at risk of this disease, which may have serious long-term consequences, including liver cancer. (See Hepatitis)

At the other end of the age-range, influenza vaccination now covers over 75 per cent of those aged 65 or older who are judged to be at high risk of complications if infected, continuing a rising trend over the past decade. However, there are other infections, where vaccination is not currently offered in the UK, such as pneumonia, that have a high death rate in this age group that are also vaccine-preventable (see Respiratory Infections).

Most modern vaccines are well tolerated, with soreness at the injection site and mild, flu-like reactions the most common side-effects. Convulsions may occur following vaccination against whooping cough, but this is rare. The main shortcomings of existing vaccines are that a small number of individuals may fail to develop a protective response to a given vaccine and that vaccines are lacking for a number of significant diseases - most notably HIV and malaria.

What's in the development pipeline?

Major suppliers of vaccines in the UK are Sanofi Pasteur MSD, GlaxoSmithKline, Wyeth and Novartis, and each of these has extensive research programmes for developing new vaccines. Other companies also active in vaccine research include Solvay, Baxter, Crucell, Xenova and Acambis. Because of the large number of projects in this field, only a selection are discussed below. Further discussion of individual vaccines will also be found in other sections of this booklet. (See Hepatitis, Herpes, HIV and AIDS, Malaria, Respiratory Infections and Tuberculosis.)

In the area of bacterial infections, GSK has a vaccine (Synflorix) against Streptococcus pneumoniae under development for prevention of respiratory infections in children (Phase 3). The same company also has a combination paediatric vaccine (Globorix) in Phase 3 trial that protects against diphtheria, tetanus, whooping cough, hepatitis B, Haemophilus influenzae type b (Hib) and Neisseria meningitis types A and C. Also in Phase 3 trial is a separate vaccine that protects against meningitis due to Hib and Neisseria meningitis types C and Y.

Following the addition of Prevenar to the routine childhood vaccination schedule, Wyeth is developing a version of this vaccine for children (Phase 3) and for 'high-risk' adults (Phase 2) that protects against a larger number (13) of bacterial strains. Novartis (Phase 2) and Sanofi-Pasteur MSD (Phase 1) are both testing vaccines against a form of meningitis (type B) for which there is no currently available vaccine. In other developments, Acambis has a vaccine in Phase 1 development against Clostridium difficile, which is the cause of widespread and difficult-to-treat infections in hospitals, and Merck Sharp & Dohme has a vaccine (MK-V710) that is directed against infection by Staphylococcus aureus, a dangerous bacterium, also in Phase 1 trial.

There is much development work ongoing in the field of viral diseases. Rotavirus is the most common cause of severe diarrhoea in children and the recent introduction of Rotarix (GSK) is a step forward. Merck Sharp & Dohme also has a rotavirus vaccine (RotaTeq), while Sanofi Pasteur has a vaccine for the prevention of transmission of cytomegalovirus from mother to baby in Phase 2 development.

Gardasil (Sanofi-Pasteur MSD) is a vaccine against four strains of human papillomavirus, the cause of genital warts and cervical cancer. Both this and the vaccine developed by GSK (Cervarix) have been shown to be highly effective in preventing new infections, and should help to reduce the incidence of cervical cancer, which causes more than 1,000 deaths a year.

Other antiviral vaccines in development target a number of tropical diseases. In Phase 3 trials, Acambis has ChimeriVax-JE, a single-dose vaccine against Japanese encephalitis, a disease affecting the brain, which is the leading cause of childhood encephalitis in Asia. Novartis also has a Japanese encephalitis vaccine (IC51) in Phase 3 trial. Acambis is also studying a vaccine against West Nile virus in Phase 2 trial, as is Vical. Hawaii Biotech is just starting Phase 1 trials with its West Nile virus vaccine. At Phase 2, GSK and Sanofi-Pasteur MSD are both working on vaccines against Dengue fever, a painful and disabling infection spread by mosquitoes. Lastly, Crucell and Vical each have vaccines in Phase 1 trial against the deadly Ebola virus, endemic in central Africa.

Therapeutic vaccines are intended to enhance the treatment of various diseases, especially cancer, and are the other focus of new developments. GSK, Oxford BioMedica, Oxxon Therapeutics and sanofi-aventis are all active in this area. GSK has a vaccine against lung cancer and melanoma (MAGE-A3) in Phase 2 trial and a vaccine against prostate cancer (P501) at Phase 1. Oxford BioMedica is developing its 5T4 vaccine TroVax for the treatment of colorectal carcinoma and renal cell carcinoma. Oxxon Therapeutics, meanwhile, has reported responses in nearly 20 per cent of patients with advanced melanoma in Phase 2 trials of its Hi-8 MEL therapeutic vaccine. Sanofi-aventis's candidate vaccine against melanoma is still at the preclinical stage.

Vaccination is likely to remain the best defence against many viral infections and, with the increase in antibiotic resistance, also against many bacterial infections. Only vaccines have the ability to both extinguish ongoing epidemics of infectious diseases and prevent their recurrence. Research into new areas such as cancer therapy represents an exciting and promising new venture with this class of medicines.