Meningococcal C immunisation will be included in the Government's national immunisation programme for the first time from November 1. This article explains the developments in vaccine technology that have made this possible
The announcement this summer by the Department of Health1,2 that a new vaccination programme for Group C meningococcal meningitis would be implemented in the United Kingdom has raised the profile of conjugate vaccines. The Hib vaccination programme achieved dramatic success in almost eradicating serious disease in children due to Haemophilus influenzae type B (see Figure). It is expected that the Group C vaccine will have a similar impact in reducing the amount of disease caused by this type of meningococcal meningitis.
Vaccines have been one of the great public health interventions of modern medicine and have saved millions of lives. Viruses are simpler structures than bacteria and effective vaccines for diseases such as polio, rubella and measles have been available for a long while. Immunisation mimics natural viral infection which often induces long-lasting immunity and antibodies correlate well with protection - or immunity. Bacteria present a greater challenge than viruses. Bacteria are in general larger and more complex organisms than viruses and their behaviour can also be more complex, including their ability to colonise the body without causing disease. Antibodies may not correlate with protection at all.
Some bacteria - for example those that cause tetanus and diphtheria - produce a toxin that is largely responsible for the disease. For this type of bacterial infection, the toxin can be used in a modified form as the vaccine. This has been done in the case of the tetanus and diphtheria vaccines we use currently. However, for some bacteria there is no single toxin which can be used to develop a vaccine. Unfortunately, this is the situation for a group of bacteria that cause some of the most common and severe infections in childhood and throughout life. These include septicaemia, meningitis, otitis media and pneumonia. The three most important examples are Neisseria meningitidis (the meningococcus), Streptococcus pneumoniae (the pneumococcus) and Haemophilus influenzae type B. Past attempts to make vaccines using traditional methods have been less successful than for other diseases, and these diseases provide the best examples of the application of conjugation to vaccine technology. For Hib there is a success story to tell, while for the meningococcus progress is so far partial and for the pneumococcus the story is still unfolding.
The bacteria for which conjugated vaccines are designed have an important structural feature in common. They are all surrounded by a thick and slippery capsule which determines to an extent their virulence. The three most common causes of bacterial meningitis - meningococci, pneumococci and Hib - are all capsulated. The capsule is made of carbohydrate and provides an antigenic target for attack by the immune system. Antibodies to the carbohydrate can be protective - they bind to the capsule and enable the white cells to destroy the bacterium. However, the immune system of children under two years of age does not respond to carbohydrate antigens. Unfortunately, this is the age group at greatest risk from bacterial meningitis. So the original vaccines that have been produced from pure carbohydrate - polyvalent pneumococcal vaccines and Group A and Group C meningococcal vaccines - are of no use in young children. Even in older children and adults, these vaccines induce only short-term immunity. Protection wanes rapidly and is generally gone by around two years from vaccination.3
The reason for this lies in the way in which carbohydrate antigens are processed by the immune system. Carbohydrate antigens are T-cell independent, meaning that the antigen is not processed by antigen presenting cells (APCs), and B cells are able to make antibodies without help from T cells. This has several consequences. This mechanism of antibody production does not develop reliably until children are around two years old. The range of antibody types produced is rather limited and no memory cells are formed so immunity is short-lived. And there is no process of affinity maturation, whereby B cells refine and improve the antibodies they produce with time.
T-dependent antigens, such as proteins, are processed by APCs and the antigen is expressed at their cell surface in complex with major histocompatibility complex (MHC) class II molecules. This induces cytokine production by T cells, which in turn triggers the development of immunity via B cells. T-dependent antigens are responded to in this way by all age groups. A wider range of antibody types are produced, and affinity maturation occurs. Importantly, immunological memory is also produced, so protection is long-term.
Conjugate vaccines are so-called because their production involves the conjugation of the polysaccharide antigen with a protein. This conjugation converts the T- cell independent carbohydrate antigen into a T-cell dependent antigen, with all the associated benefits in terms of immunological response.4
Various protein carriers have been used for conjugation, including diphtheria and tetanus toxoid. The different formulations have been shown to have varying levels of immunogenicity, as measured by antibody response. Another factor which has been demonstrated to affect the immunogenicity of the vaccines is the adjuvant which may be present in combined vaccines. Lower immunogenicity has been observed for Hib vaccines which are mixed with DTP vaccines with aluminium hydroxide compared with those with aluminium phosphate.5
The great success story with conjugate vaccines starts with Hib (see Figure). Dramatic success has been observed in the reduction of disease, including meningitis, bacteraemia and epiglottitis. This has been attributed in part to interruption of transmission of the bacteria, with lower observed rates of carriage of the organism in the nose and throat of children. Similar success might be anticipated for meningococcal and pneumococcal disease but the problems are more complex for these organisms.
N meningitidis has many different serogroups but groups B and C account for the majority of the cases in the UK. A group C conjugate vaccine is now being introduced to the UK because Group C has increased as a proportion of cases in recent years and now accounts for 40 per cent of cases of meningococcal disease.1 The new conjugate vaccines use either diphtheria toxin or tetanus toxoid as the protein carrier.6
Group B meningococcus causes more disease than C, but its capsule is poorly immunogenic and so a vaccine is not yet available. The lack of immunogenicity is attributed to the similarity between the antigens and some elements of human brain tissue - the immune system is therefore tolerant of the antigens as it regards them as part of "self". Different approaches are being taken to overcome this.
The burden of pneumococcal disease is enormous, including septicaemia, pneumonia and meningitis in all age groups. The need for an effective vaccine is underlined by the increasing antibiotic resistance that is being observed world-wide. The challenge presented by the pneumococcus for vaccine development is in some ways greater than that presented by Hib and the meningococcus. Both the meningococcus and the pneumococcus have many different serogroups but in the case of the meningococcus most cases of infection are caused by a small number of common serogroups and vaccination can be targeted to the types that account for the vast majority of disease.
In contrast, the burden of disease caused by the pneumococcus is spread more evenly across a large number of serotypes. The capsular antigens of 23 different types of pneumococcus are used in the existing unconjugated polyvalent pneumococcal vaccine. This is recommended for those over two years of age with chronic heart, lung, liver and renal disease, diabetes mellitus, sickle cell disease, splenic dysfunction and immunosuppression.3 Technical limitations mean that it is not possible yet to have so many serogroups in a conjugated vaccine. However, large efficacy trials of conjugate pneumococcal vaccine in children have had extremely encouraging results.7
The potential for new technologies to produce amazing improvements in public health are well demonstrated by conjugate vaccines. The day may come when infants receive one "meningitis vaccine" along with their other primary immunisation. New conjugated vaccines are expected in the next few years. Before these can be integrated into immunisation programmes, careful clinical, laboratory and epidemiological work needs to be carried out to ensure that no interference occurs between vaccine preparations and that the vaccines are used appropriately in the right age groups to maximise the benefit for the public's health.8,9
The advent of conjugate vaccines may herald a new age for vaccines. They bring the possibility of preventing common bacterial infections for which vaccines produced with older technologies were ineffective in those most at risk - infants - and induced only short-term protection in everyone else.
Dr Crowcroft is a specialist in public health medicine in the immunisation division of the Public Health Laboratory Service Communicable Disease Surveillance Centre, London