Update on childhood immunisations

Summary
Childhood immunisation with new and existing vaccines is undergoing exciting changes. The controversy concerning the frequency and severity of adverse reactions to pertussis vaccine is now largely settled. There is overwhelming evidence of the benefits of pertussis vaccines and there are promising developments with acellular vaccines. Lists of contraindications and precautions have been drastically reduced and, with improved surveillance of immunisation, there is the potential for greater vaccination coverage. Vaccines against Haemophilus influenzae type b (Hib) are now included in the immunisation schedule and promise virtually to eliminate this important childhood infection.Universal infant immunisations against hepatitis B have been recommended in the U.S.A. In Australia, targeted immunisation is still recommended, but may be replaced by universal immunisation of school-age children or infants in the future. Combination vaccines for triple antigen, Hib and hepatitis B are at an advanced stage of evaluation. The medical profession should be at the forefront of promoting immunisation at every opportunity as one of the most effective health interventions available.

Introduction
Childhood immunisation programs have been one of the outstanding public health successes of the past 50 years. The greatly diminished incidence of vaccine-preventable diseases has led to increased community concern about possible adverse effects of immunisation. However, continued outbreaks of measles and pertussis have reminded us that the level of vaccine uptake in the Australian community is still inadequate. Clinicians have to meet the challenge of being better informed to assist a generation of parents who often have no experience of the diseases prevented by immunisation and who are increasingly concerned about the adverse effects of vaccines. There will also be the challenge of an increasing number of new vaccines in the coming decade.

Adverse reactions to vaccines
It is important when talking to parents about possible adverse reactions to vaccines both to acknowledge that they can occur and to emphasise the much more frequent and severe complications of natural disease. A recent Canadian study found that 61% of mothers preferred a numeric statement about vaccine risks, whereas 73% of doctors predicted that their patients would prefer qualitative statements.¹ A booklet for parents with tables comparing the risks of disease and vaccination is available from the New South Wales Department of Health.²

Pertussis
Public concern about brain damage after pertussis immunisation has been highly detrimental in many countries. In the U.K., adverse publicity led to a marked fall in pertussis vaccine uptake in the late 1970s, while other countries such as Sweden (1979) and Japan (1975) abandoned pertussis immunisation altogether. In Japan, the number of pertussis cases and deaths rose from 206 and 5 respectively in 1971 to 1305 and 41 in 1979.³

It has been very difficult to evaluate the significance of neurological problems following pertussis immunisation for a number of reasons:

• serious acute neurological events occur in the first year of life with or without immunisation
• there are no symptoms or signs specific for pertussis encephalopathy
• it is often difficult to know whether infants below 6 months of age were previously neurologically normal

A committee was set up by the U.S.A. Institute of Medicine to examine the evidence for serious adverse reactions following immunisation under the U.S. National Childhood Vaccine Injury Act.⁴ The committee's conclusions are shown in Table 1.

The committee judged that if chronic brain damage due to pertussis immunisation occurred at all, it was so rare that it was impossible to study.

Rubella
The committee also examined rubella vaccine and found that there was a 13-15% rate of acute arthritis in adult women following rubella vaccine, compared to 30-40% following natural rubella, and very low rates in children, adolescents and adult males. The committee was unable to make reliable estimates for chronic arthritis following rubella vaccination.

Contraindications to immunisation
The negative impact of 'vaccine myths' or non-contraindications on immunisation uptake has been increasingly recognised; a full list appears in 'Immunisation Procedures'.⁵ Three common misunderstandings are worthy of correction:

• it is not necessary to recommence a course of immunisations if more than the recommended time between doses has elapsed
• mild acute illness is not a reason to defer immunisation
• a family history of seizures or febrile seizures is not a contraindication

Minor illness often results in 'missed opportunities' for immunisation, where children presenting to general practice or hospital casualty departments for other reasons could be immunised. A recent survey in a Sydney casualty department found that more than 80% of parents were happy for their children to receive overdue immunisations.⁶ A family history of febrile seizures increases the risk of a fit with any cause of fever including pertussis vaccine. However, febrile seizures are unusual in children under 6 months of age, hence febrile seizures are a more likely complication of measles, mumps, rubella vaccine (MMR) at 12 months or the 18 month triple antigen (DTP) booster. The Australian College of Paediatrics encourages the routine use of paracetamol in all children. Studies have shown that a dose range of 10-15 mg/kg at the time of immunisation and every 4 hours for 3 or 4 doses is effective. This may also prevent many cases of protracted crying which are often related to pain from local reactions. Maintaining full feeds is also important after triple antigen as there is evidence to suggest that transient hyperinsulinism induced by pertussis toxin and consequent hypoglycaemia is responsible for some adverse reactions.

Excessive and complicated lists of contraindications are now recognised as an important barrier to achieving adequate levels of immunisation. The only well established contraindications to active immunisation are:

• concurrent moderate to severe illness (where it is unlikely that parents would present for immunisation)
• a previous anaphylactic reaction to that vaccine or severe hypersensitivity to a vaccine constituent, such as egg protein in measles vaccine
• attenuated live vaccines (such as BCG, MMR and oral poliomyelitis vaccine (OPV)) in immuno compromised patients.

There are qualifications even to these limited contraindications - children with suspected egg hypersensitivity can usually be safely immunised under close observation, such as in a paediatric casualty department, and certain immuno compromised children may be given live vaccines if the benefits outweigh the risks (e.g. HIV-infected children and measles vaccine).

Pertussis is a significant risk to children with neurologic handicap because of an increased incidence of respiratory complications e.g. aspiration, pneumonia. Delaying immunisations in children whose neurologic status is initially unclear is often a better option than giving diphtheria and tetanus toxoid (CDT), as exposure to diphtheria and tetanus is extremely unlikely in the first year of life and if a full course of CDT has been given, subsequent triple antigen would carry an unacceptably high risk of systemic reaction. This should be less of a problem now that the monovalent pertussis vaccine is available. Use of CDT vaccine has been far too high in many areas of Australia, encouraged by its availability as a 'Doctor's Bag' item. The availability of free triple antigen to general practitioners under the National Immunisation Strategy would help remedy this.

New ways with old vaccines
Measles mumps rubella vaccine (MMR)

a) Age of immunisation
The recommended age for measles immunisation was 15 months, because of U.S.A. evidence of lower sero conversion rates at 12 months due to residual maternal antibody. However, an Australian study has found equivalent immunogenicity at 12 and 15 months.⁷ MMR is now given at 12 months which is an easier date to remember. There is some evidence that as more women of childbearing age have vaccine-acquired rather than natural immunity to measles, measles is becoming more common in children under 12 months of age. It is possible that even earlier immunisation, possibly with vaccines of enhanced potency, will become necessary in the future.

b) Two dose MMR schedule
In 1992, the National Health and Medical Research Council (NHMRC) recommended that a second dose of MMR for all children at 12 years of age replace the schoolgirl rubella immunisation program. This followed a similar recommendation in the U.S.A., and was based on concern that the 3-5% of children who did not seroconvert after MMR in infancy could allow measles outbreaks to occur.

The risk of adverse effects from MMR is not increased in individuals who are already immune. This is important for infant immunisation as a parental report of previous measles was the most common reason for non-immunisation in a Western Australian study⁸, but many infants who are diagnosed as having measles actually have another diagnosis such as enteroviral infection. Even if a child has had serologically confirmed measles, it will usually be more convenient to give MMR, rather than separate mumps and rubella vaccines.

Pertussis vaccine
A fifth dose of pertussis vaccine before school entry is currently recommended in the U.S.A. This is also advocated by the Australian College of Paediatrics, in view of the waning immunity by 3 years post-immunisation and the importance of school age children in pertussis transmission. The availability of acellular pertussis vaccines, with reduced febrile and other adverse reactions, will make this proposal even more attractive. Acellular pertussis vaccines have already been licensed in the U.S.A. for use at 18 months of age and above.⁹ An acellular pertussis vaccine could also be included in tetanus-diphtheria-pertussis boosters for adults, who may also be an important reservoir of infection, especially as vaccine-acquired immunity replaces natural immunity.¹⁰

Polio vaccines
With the near eradication of wild polio in developed countries, vaccine-related polio is becoming a more important, though rare, problem. Inactivated polio vaccines of enhanced potency are now available and should be used readily if the patient or family contacts are immuno compromised. Inactivated polio vaccines are being considered for either whole or part of the polio immunisation schedule, especially if they can be delivered at a comparable cost to oral polio vaccine in a combined preparation.

New vaccines
Haemophilus influenzae type b (Hib)
Before immunisation was introduced in 1993, Hib was the most common cause of serious bacterial infection requiring hospitalisation among Australian children, with 600-700 children under 5 years of age hospitalised with invasive Hib disease each year. Approximately 300-400 have meningitis, resulting in an estimated 50 children dying or suffering long-term disabilities.¹¹ There is already evidence from a number of areas of Australia that the incidence of invasive Hib disease has markedly declined in the last half of 1993, following inclusion of Hib vaccine in the infant immunisation schedule and catch-up programs among older children.

The four available conjugate Hib vaccines are effective and have few adverse effects.¹² The vaccine chosen for the Australian program, PRP-CRM (HibTITER), is the most commonly used conjugate Hib vaccine worldwide and has an excellent record of safety and efficacy. The PRP-OMP vaccine (PedvaxHIB) was chosen for immunisation of Aboriginal children because of evidence that it induces protective immunity after the first dose, which may be important in Aboriginal populations with very early disease onset. There is no evidence that either vaccine is superior in the case of non-Aboriginal children. Children who started immunisation with a vaccine other than HibTiter can complete their course with that vaccine at government expense. Although it has been recommended that Hib immunisation should be completed with the same vaccine, there is accumulating evidence that immune response is not reduced and may even be enhanced by 'mix and match' schedules.¹² It is therefore the author's personal view that children inadvertently immunised with different Hib vaccines need not have the course repeated. All Hib vaccines can be given at the same time as other routine vaccines, but at a different site. In infants, they should be given in the opposite thigh to triple antigen and, over the age of 12 months, in the opposite arm. Most local reactions and fever are attributable to the simultaneous injection of triple antigen.

Hepatitis B vaccines
In 1991, the American Academy of Pediatrics and the Immunisation Practices Advisory Committee of the U.S.A. Centers for Disease Control recommended that a policy of universal immunisation of infants against hepatitis B replace the targetted immunisation of risk groups.¹³ This decision was based on 4 considerations:

• the failure of the targetted program to reduce the incidence of hepatitis
• the lifetime morbidity of hepatitis B is high; although fewer cases occur in children, they are more likely to become chronic carriers
• 40% of acute hepatitis B cases in the U.S.A. had no recognised risk factors
• infants are much more readily accessible for immunisation than adolescents or adults and can be immunised with lower doses of vaccine

Of course, the socio demographic circumstances of Australia are substantially different from the U.S.A., but at least some of these considerations are likely to apply here. The argument against universal infant immunisation is the almost negligible incidence of hepatitis B infection (prior to adolescence) in children from low-risk groups in Australia and concern about the duration of immunity.

Current hepatitis B vaccines are recombinant, not plasma derived, and are immunogenic and protective after 3 doses in infants. The problems to be resolved are cost and the differences between the timing of hepatitis B vaccine (0, 1 and 6 months) and other current vaccines. Despite some suggestions to the contrary, there is no evidence in Australia of horizontal transmission of hepatitis B outside the family e.g. at school. Nevertheless, it is the author's view that difficulties in delivering 3 doses of vaccine to older children will make infant immunisation the most practical alternative if combination vaccines become available at an acceptable cost.

The need for and timing of booster doses in the general community is unresolved. Protection against persistence of HBV infection may persist well after protection against acute infection, making booster doses less necessary on a population basis. Individuals who have a poor antibody response after the initial course of immunisation are also most likely to have rapid loss of antibody. However, post-immunisation serology is only worthwhile for high risk groups, such as household contacts of carriers and medical and nursing personnel who have significant hepatitis B exposure.

Varicella vaccine
A vaccine against varicella, based on the Japanese OKA strain, has been used in clinical trials since 1973, but at present is not available for use in Australia. Based on various studies, approximately 90% of healthy children, 85% of leukaemic children and 70% of healthy adults are protected against varicella after immunisation. As 95% of children have had varicella by the age of 18 years, this vaccine has the potential to prevent a large number of infections which often have considerable morbidity. Immunisation in childhood is clearly preferable, as adults have much lower sero conversion rates and experience much greater morbidity and mortality from varicella. The major concern with regard to routine immunisation against varicella is the limited duration of immunity with the risk that children might again be susceptible after reaching adult life, if the virus is still circulating in the community. There is no evidence of an increased risk of zoster. It may be decreased by immunisation.

Hepatitis A vaccine
A recent controlled trial of an inactivated hepatitis A vaccine in a New York Jewish community with a high incidence of hepatitis A infection has shown 99% sero conversion after a single dose among children aged 2-16 years.¹⁴ It is possible that the vaccine will also prove of value after exposure to hepatitis A, as an alternative to immunoglobulin. Hepatitis A vaccine, which has been available in Australia since 1993, will be useful for adults at increased risk of infection, such as child care workers, workers in institutions for the intellectually disabled and male homosexuals, as well as travellers. Young children probably do not need hepatitis A immunisation before travel as the disease is generally asymptomatic or mild under 5 years. Adults are well advised to have serology for hepatitis A performed before immunisation as testing is less expensive than the vaccine.

Other vaccines
There is ongoing research into vaccines for other important childhood viral illnesses such as rotavirus diarrhoea and respiratory syncitial virus infection. Pneumococcal conjugate vaccines, in particular, may prove suitable for general use in a similar fashion to Hib vaccines, if they are found to be protective against otitis media and pneumonia as well as bacteraemic infections.

Combination vaccines
The expanding number of potential infant immunisations has prompted great interest in combined vaccines to decrease the number of injections and simplify schedules. Combinations of triple antigen with Hib and hepatitis B vaccines have been developed. One combination vaccine including triple antigen and Hib has been licensed for use in the U.S.A. and is proposed for general use in New Zealand, where universal hepatitis B vaccination is routine. A varicella vaccine for general use would most likely be included with MMR as MMR-V. Combined vaccines may substantially reduce the costs of vaccines and vaccine delivery. At least in the short term, vaccine costs are likely to be a major hurdle to general introduction of both combined vaccines and new vaccines such as varicella and acellular pertussis vaccines. At present, the most important challenge is to improve the uptake of currently recommended vaccines to 95% or more of the target population to eliminate the serious diseases against which they protect.

NHMRC standard childhood vaccination schedule

a) HbOC (HibTITER)
b) PRP-T (Act-HIB)
c) PRP-OMP (PedvaxHIB)

Note that a fourth Hib vaccine [PRP-D (ProHIBit)] is approved for use as single injection for children over 18 months of age.

* recent changes to the schedule