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The New Zealand Medical Journal

 Journal of the New Zealand Medical Association, 23-June-2006, Vol 119 No 1236

Evolution of the New Zealand Childhood Immunisation Schedule from 1980: a personal view
Stewart Reid
Abstract
A personal view of the evolution of the New Zealand immunisation schedule (from the perspective of someone who has been involved in the decision-making process since 1980) is presented in this article. The rationale behind changes to vaccination strategies to control pertussis, hepatitis B, polio, measles, mumps and rubella, and Haemophilus influenzae type b are presented. Finally brief comment is made on the National Immunisation Register and the likely vaccines to be introduced into the schedule in the foreseeable future.

I first became involved in the committee which advises Government on immunisation policy in 1980 and have remained involved since then, chairing the committee in its various incarnations for much of the time since 1985. I am therefore in a unique position to describe the rationale behind the various changes in immunisation policy which have taken place in the last quarter century.
In 1996, a history of the New Zealand Immunisation Schedule was published.1 This information is also summarised in the New Zealand Immunisation Handbook by both vaccine and schedule.2 Dow and Mansoor1 stated that their account “only provides a superficial explanation for the reasoning behind each change”. I propose to provide greater detail on the rationale behind the changes I consider most important.
In my opinion, the key changes to the vaccine schedule, since 1980, have been to pertussis vaccination, with an increase from two to five doses and a change from whole cell to acellular pertussis vaccine. In addition, the introduction of hepatitis B, measles, mumps and rubella (MMR), and Haemophilus influenzae type b (Hib) vaccines and the change from oral (live) polio vaccine (OPV) to inactivated polio vaccine (IPV) have also been significant.
With these changes, there have been consequential changes to the combination vaccines used and the timing of the schedule. Finally the recently introduced National Immunisation Register (NIR) is arguably the most important development in immunisation in New Zealand in the last 25 years. (Group B meningococcal vaccine, MeNZB, is not covered in this article as it is a vaccine that has been introduced specifically for epidemic control and is not considered part of the routine childhood immunisation schedule.)

Pertussis (whooping cough)

In 1980, the pertussis schedule was for two doses of pertussis vaccine at 3 and 5 months of age. A third dose was added in 1984, a fourth dose in 1996, and a fifth dose in 2002. The change to acellular pertussis vaccine was made in 2000, and the timing of the five-dose schedule was altered in 2006, with the fourth dose changing from the second year of life to age 4 and the fifth dose from age 4 to age 11.
The initial schedule, introduced in 1960, was of three doses of plain (i.e. no aluminium adjuvant) diphtheria, tetanus, and pertussis (DTP) vaccine administered at 3, 4, and 5 months of age. When vaccine with aluminium hydroxide adjuvant became available in 1971, the 4-month dose was omitted as it was felt that the two doses of adjuvant vaccine would provide similar protection to three doses of plain vaccine and exhibit fewer adverse effects.1
In 1982, when the standard schedule was two doses, there was a large epidemic of pertussis with several deaths.3 There were two aspects to the debate which took place in the Epidemiology Advisory Committee. Firstly was the number of doses in the schedule inadequate? It was pretty clear that this was the case and a third dose administered in the first 6 months of life was required.
Secondly, when should the third dose be administered? In general, it was felt it should be administered as early as possible and 4 weeks of age was considered. At that time, most general practitioners (GP) were involved in maternity care and most mothers and infants attended their GP for a postnatal visit at 6 weeks of age. Accordingly, 6 weeks was chosen as it was thought high coverage of this first dose would be achieved.
This decision led to the unique timing (6 weeks plus 3 and 5 months) of the New Zealand infant immunisation schedule. The decision created an unforeseen and recurring problem for the licensure of most vaccines in New Zealand as almost no vaccine studies utilise the New Zealand schedule. For licensure of most vaccines, it has therefore had to be assumed that if a vaccine provides protection (when administered at 2, 4, and 6 months and at 2, 3, and 4 months) then it will provide similar protection when administered at 6 weeks plus 3 and 5 months.
The fourth dose of pertussis vaccine was added in 1996 by utilising the combination vaccine DTPH (diphtheria and tetanus toxoids, whole cell pertussis vaccine, and Haemophilus influenzae type b conjugate vaccine). It had become clear that three doses of pertussis vaccine in infancy were insufficient to control all pertussis in the community.
Children who have received three doses of vaccine are well protected against typical pertussis till at least the age of 4 years.4 However, as immunity from either pertussis disease or vaccination wanes over time, it is possible that older siblings in a household could be infected with pertussis and pass on the infection to infant siblings not yet old enough to have been protected by vaccination. It was anticipated that a fourth dose at 15 months would provide protection against milder disease and increase the effectiveness of the vaccine course and the duration of immunity.4
In 1992, a coverage survey was conducted5 which indicated low rates of on-time coverage for those aged less than 2 years. This 1996 schedule change, using the combination DTPH vaccine, involved the deletion of the 18-month, 5-year, and 15-year visits without reducing the number of doses of any vaccine.
Vaccine doses previously administered at age 5 and 15 years were combined and given at age 11. A dose of OPV was given at 6 weeks instead of 18 months, so that the primary course of three doses of OPV was completed in the first 6 months of life.
It was anticipated that this “streamlining” of the schedule would allow GPs and practice nurses to concentrate on delivering the three visits in infancy and the fourth at 15 months, thus leading to an increase in on-time coverage, whilst the public health service would administer the 11-year visit in schools.
The 1980, 1984, 1994, 1996, 2000, 2002, and 2006 schedules are shown in Table 1.

Table 1. New Zealand Immunisation Schedules

1980

DTP
OPV
Measles
DT
Rubella
Tetanus
3 months
X
X




5 months
X
X




12 months


X



18 months

X

X


5 years

X




11 years




Girls only

15 years





X

1984

DTP
OPV
Measles
DT
Rubella
Tetanus
6 weeks
X





3 months
X
X




5 months
X
X




12–15 months


X



18 months

X

X


5 years

X




11 years




Girls only

15 years





X

1994

DTPH
Hep B
OPV
MMR
DT
Hib
Td
6 weeks
X
X





3 months
X
X
X




5 months
X

X




12–15 months

X

X



18 months


X

X
X

5 years


X




11 years



X



15 years






X

1996

DTPH
Hep B
OPV
MMR
Td
6 weeks
X
X
X


3 months
X
X
X


5 months
X
X
X


15 months
X


X

11 years


X
X
X

2000

DTaP
Hib-HepB
Hep B
DTaP-Hib
OPV
MMR
Td
6 weeks
X
X


X


3 months
X
X


X


5 months
X

X

X


15 months



X

X

4 years




X
X

11 years






X

2002

DTaP-IPV
Hib-HepB
Hep B
DTaP-Hib
MMR
Td
6 weeks
X
X




3 months
X
X




5 months
X

X



15 months



X
X

4 years
X



X

11 years*





X

2006

DTaP-IPV
Hib-HepB
Hep B
Hib
MMR
dTap
6 weeks
X
X




3 months
X
X




5 months
X

X



15 months



X
X

4 years
X



X

11 years*





X
* IPV administered at this visit to children who have not already received 4 doses of a polio vaccine.

The change to acellular pertussis vaccine in August 2000 was made necessary by a failure in supply of the DTPH vaccine. However, it simply brought forward a planned change; acellular pertussis vaccines are significantly less reactogenic than whole cell vaccines and provide comparable protection.
During the 1990s, several major studies of the efficacy of acellular pertussis vaccines were published and supported the licensure of these vaccines, including those used in New Zealand.6–9 This change in vaccine also resulted in a huge reduction in the number of antigens administered to infants; whole cell pertussis vaccine has about 3000 individual antigens whilst the acellular pertussis-containing vaccine, Infanrix,™ has only three antigens.10
A change in the Hib vaccine, and its combination with hepatitis B vaccine, avoided an increase to three in the number of injections required at each vaccination visit. (See also below under Hib.)
In 2002, a fifth dose of pertussis vaccine was added at 4 years of age. The rationale for this change was to further extend the duration of protection conferred by the vaccine course making it less likely that older siblings would bring pertussis into a household and infect a very young infant.
In 2006, five doses of a pertussis containing vaccine will continue to be administered, but the timing will change. Data from the Italian efficacy study, in which Infanrix™ was one of the vaccines, indicate that protection following three doses in infancy is stable for about 6 years.11 This means that the dose in the second year of life is redundant and can be omitted. The dose at 4 years therefore becomes the fourth dose, and the fifth dose is administered at 11 years to further extend the duration of protection.
The vaccine administered at 11 years is the adult formulation of diphtheria tetanus and acellular pertussis vaccine, with a reduced content of diphtheria toxoid and the pertussis antigens

Hepatitis B

In 1985, the first plasma-derived hepatitis B vaccine was offered to babies born to high-risk, HbeAg-positive mothers. In 1987, the use was extended to all surface antigen (HBsAg)-positive mothers and all newborns in districts deemed to be at high risk, mostly in the north of New Zealand. Then, in 1988, a universal vaccination programme was introduced using firstly, four “low” doses of plasma-derived vaccine and, from December 1989, three “full” doses of recombinant vaccine, as is currently used.
The reason for this slow progress was fiscal. Milne and Moyes12,13 had drawn attention to the high rate of hepatitis B in New Zealand and, in particular, Sandor Milne promoted hepatitis B vaccination, putting considerable pressure on the Ministry of Health and Government to fund a programme. However plasma-derived hepatitis B vaccine, which was highly immunogenic, was also very costly resulting in this cautious introduction.
Milne and Moyes14 conducted studies using low-dose, plasma vaccine: 2 µg instead of 10 µg. This lower dose, although stimulating a high rate of seroconversion, induced a lower antibody titre than three doses of 10 µg. The Committee, at the time, was concerned about the lower antibody levels but was persuaded to recommend a universal low-dose regimen with a fourth dose at 15 months when Milne and Moyes demonstrated that the fourth dose stimulated very high titres indeed.14
In hindsight, the Committee was wrong to be so concerned about the height of the antibody response as it is now accepted that having seroconverted (attained a titre of > 10 MIU/ml) against hepatitis B is sufficient to confer long-term protection against clinical disease.15
The other key point that has been discussed over the years is whether there should be a universal birth dose of hepatitis B vaccine. In general, universal vaccine programmes work better than targeted programmes—i.e. fewer eligible individuals miss out. The argument for a universal birth dose is that this is the best method of ensuring that those at greatest risk (i.e. babies born to carrier mothers) are protected.
The argument against a universal birth dose is that as the majority of children do not require it, many providers and parents would opt not to give it, and this would result in confusion and poor overall coverage. This latter argument has, to date, prevailed in New Zealand.

Oral polio vaccine – inactivated polio vaccine

In 2002, the preferred polio vaccine was changed from oral (live) polio vaccine (OPV) to inactivated polio vaccine (IPV). There is no doubt that OPV has been responsible for the eradication of wild polio from the Western Pacific region, including New Zealand.16 However indigenous cases of clinical polio have continued to occur in New Zealand with four confirmed and two probable cases since 1962.17
The confirmed cases have all been caused by vaccine-derived strains which can, in rare instances, revert to neurovirulence and cause clinical polio. Indeed, in countries where OPV is used with high coverage, clinical polio is almost always caused by strains derived from the vaccine virus. The rate at which this occurs is about 1/750,000 first doses of OPV.
Of the two cases which occurred in New Zealand in 1998, one was in a child who had received two doses and the other in an unimmunised mother following her infant’s first dose of vaccine. These two cases led to the then Vaccine Advisory Committee firming up on its previously considered recommendation to change from OPV to IPV. The availability of a combination DTaP-IPV vaccine avoided the need to increase the number of injections required at each vaccination visit to three injections.

Measles mumps and rubella – MMR

Prior to 1990, single antigen measles vaccine was given to all children at 12–15 months and rubella vaccine was given to girls in school year 7 (children aged approximately 11 years). MMR vaccine was introduced in 1990 when it was given to all children at 12–15 months. A universal second dose at 11 years, replacing the so-called schoolgirl rubella vaccine programme, was introduced in 1992. In 2001, the timing of the second dose was changed from 11 years to 4 years.
There is little doubt that, with sufficiently high coverage, especially for the first dose, the two-dose strategy in place now is likely to lead to the elimination of indigenous measles, mumps, and rubella in New Zealand, as has been seen in Scandinavia.18 However it has been a long road dominated by considerations of how best to control congenital rubella and measles, with the control of all rubella and mumps secondary considerations.
Rubella vaccine was offered from 1970 to all children at 4 years of age. Because uptake was poor in boys, this was changed to vaccination targeted at girls at age 11 in school year 7, prior to reproductive age. This was the UK approach to the control of congenital rubella. The argument supporting this strategy being that if high coverage was achieved, which it was in New Zealand, continued exposure to wild rubella would ensure that, for those vaccinated, immunity would be regularly boosted, thus providing protection to a high percentage of women in pregnancy.
Continued exposure to wild rubella would occur because no-one under age 11 and no males were vaccinated. The alternative strategy, used in the US, was universal childhood vaccination reducing the likelihood of anyone, in particular a pregnant mother, being exposed to rubella.
Both strategies significantly reduce, but do not eliminate, congenital rubella syndrome. In New Zealand, it became accepted that, because not all year-7 girls would be vaccinated and not all those vaccinated would respond, there would always be a small number of women in pregnancy susceptible to rubella.
Because rubella continued to circulate, there would continue to be cases of congenital rubella syndrome. The solution for New Zealand (and incidently the UK and the US) was therefore to adopt the Scandinavian universal two-dose strategy, with a first dose in the second year of life and a second dose at either 4 to 6 years or 11 years.
The purpose of the second dose was to immunise those who had either missed out on, or failed to respond to, the first dose. This strategy ensured that, with high coverage, the maximum percentage of the female population was immune and for those who either failed to be vaccinated or failed to seroconvert, the likelihood of them confronting wild rubella was remote. The two-dose strategy also enabled excellent control of measles and mumps with the second dose providing an opportunity to vaccinate those who had missed out on, or failed to respond to, the first dose.
The second dose was given at age 11 because of the high coverage which had been obtained in the schoolgirl rubella programme. The timing of this second dose was changed to 4 years in 2002 because computer modelling demonstrated that this timing made control of measles, and eventual elimination, easier.19,20 Very high coverage with both doses (in particular the first dose) is essential, however. It is unlikely there will be any change to the MMR strategy for the foreseeable future, though if coverage is low, catch-up campaigns may be required.

Haemophilus influenzae type b – Hib

Hib vaccination was first introduced in 1994 when it was administered as a component of the quadrivalent vaccine DTPH. The preferred Hib vaccine changed in 2000 and was administered as a Hib-hepatitis B combination vaccine.
Prior to vaccination, Hib was a common cause of invasive bacterial disease. Early Hib vaccines were derived from the polysaccharide capsule of the organism, polyribosylribitol phosphate (PRP). These vaccines were poorly immunogenic in infants aged less than 2 years and, like other polysaccharide antigens, did not induce immune memory. Indeed, if invasive Hib disease occurs in a child aged less than 2 years, the child is likely to remain susceptible.
The solution to this problem was to attach (conjugate) the PRP to a protein carrier. This meant that infants could mount an immune response against the PRP and develop immune memory—i.e. the conjugated vaccine would stimulate a better immune response than the organism induces in infants.
Furthermore, conjugate Hib vaccines induce a high level of mucosal antibody-lowering carriage rates, and reducing the likelihood of susceptible individuals being exposed to the organism. This means that the effectiveness of the vaccine in practice may be greater than would be predicted from the efficacy observed in a clinical trial and the coverage attained in a community.
The first Hib vaccine introduced to the New Zealand Childhood Immunisation Schedule was HbOC in which the protein conjugate was a mutant diphtheria toxin, the so called CRM197. It was highly immunogenic after three doses in infancy and a booster dose given in the second year of life. This vaccine has been shown to be protective, with efficacy of 100% after three doses in a clinical trial conducted in a community in Northern California.21
The decision to introduce Hib vaccine was not difficult given that New Zealand had, prior to vaccination, in excess of 100 cases of invasive Hib disease each year and that there was a highly efficacious and safe vaccine available. Its introduction in 1994 had been delayed by around 2 years, pending the availability of the combination DTPH vaccine (Tetramune), to avoid the necessity of giving three injections at a single visit.
HbOC reduced the incidence of Hib in New Zealand very significantly but the percentage of cases occurring in those aged less than 6 months of age increased.22 Because of this, when the supply of DTPH failed, the opportunity was taken to change to a vaccine containing PRP conjugated to an alternative protein carrier, PRP-OMP, which provides earlier protection because it induces a protective immune response following the first dose.
PRP-OMP is a Hib vaccine in which PRP is conjugated to the Neisseria meningitidis outer-membrane protein. Only two doses are required in infancy, and a significant immune response occurs after a single dose. Efficacy, calculated in a trial conducted in an American Indian Navajo community, was 100% until 15 months of age in any child who had received either one or two doses in infancy, and 95% for all children with a single failure occurring at 15.5 months of age.23
Because of its first-dose response, this vaccine should be used for at least the initial dose(s) in any community in which there is a significant burden of disease in those aged less than 6 months, as in New Zealand. Since the introduction of this vaccine, the percentage (and number) of cases under 6 months of age has reduced (Immunisation Handbook 2006; in press).
New Zealand has always administered a booster dose of a Hib vaccine in the second year of life to boost antibody levels, to extend protection till at least age 5, covering the highest risk years, and to provide the best control of the disease.24,25 The precise vaccine used has generally been determined by the combination vaccine most suitable for administration at 15 months. Currently, a tetanus toxoid conjugate (PRP-T) is administered at 15 months as a single-antigen vaccine. This vaccine is preferred because a single booster dose at 15 months produces high antibody titres.

The National Immunisation Register

The National Immunisation Register (NIR) is one of the most important developments in immunisation in New Zealand in the past 25 years. In New Zealand, it has been rolled out, district by district, from 2005 onwards, enrolling children from birth. It will allow the accurate measurement of coverage, and should assist with an increase in coverage by identifying individuals and pockets of low coverage where greater effort can be targeted. It will provide important data for the future development of New Zealand immunisation policy, which has been hampered by not having up-to-date reliable coverage data.
If a vaccine programme fails to adequately control its target disease, this may be because either the vaccine is not efficacious or the programme not effective. Without accurate coverage figures, it is not possible to make this distinction.
The NIR was essential for the safety monitoring of MeNZB™ vaccine. It uses the same unique identifier, the National Health Index number (NHI), as used by providers in hospital and primary care, thus enabling the tracking of adverse events following immunisation. It also enabled the identification of those who had subsequent doses following an adverse event, providing re-challenge data, which is seldom available for adverse events following immunisation.
The NIR could potentially be a very valuable tool for the monitoring of the safety of all vaccines in New Zealand, particularly for conditions which require hospitalisation, because of the ability to link the hospital-discharge database to the immunisation data base using the same unique identifier.

The future

There are many new vaccines under development and it will be an ongoing challenge to decide whether to incorporate them into the routine schedule. It is likely that more vaccines will be promoted by vaccine-manufacturing companies for private administration, and this will present a challenge for those in primary care to be sufficiently well-informed to advise parents and caregivers well.
On the immediate horizon are pneumococcal conjugate, group C meningococcal conjugate, varicella, rotavirus, and human papilloma virus (HPV) vaccines. As well as the clinical justification and the cost-benefit rationale for these vaccines, there are the administration difficulties. Rotavirus vaccines are oral vaccines and so their administration should not cause too many problems. HPV vaccine, the second cancer-preventing vaccine after hepatitis B vaccine, will be administered in adolescence (prior to sexual activity), and this may meet some resistance. Varicella is likely to be administered as a component of a combination MMRV vaccine.
While using MeNZB, three injections are required to be administered simultaneously at each of the first three visits. As well, both pneumococcal and meningococcal vaccines require at least two intramuscular doses in infancy and they are not yet available as combination vaccines. It is therefore very likely that the addition of these new bacterial vaccines will result in a further increase in the number of injections required at each visit. Such recommendations will have to be very carefully considered by policymakers.

Conclusion

The past 25 years have proved to be a very interesting time in the evolution of the New Zealand Immunisation Schedule, with many changes. It is likely that the pace of change will increase and that vaccination will be available and offered against a larger number of vaccine-preventable diseases. The creation of the NIR will help ensure that New Zealand gains the maximum benefit from the introduction of new vaccines.
Author information: Stewart Reid, General Practitioner, Ropata Medical Centre, Lower Hutt
Acknowledgements: I am grateful to Rod Ellis-Pegler and Mark Thomas of Auckland University as well as Nikki Turner, Natalie Desmond, and Helen Petousis-Harris of the Immunisation Advisory Centre, University of Auckland for their critical review of the manuscript.
Correspondence: Stewart Reid, General Practitioner, Ropata Medical Centre, 577 High Street, Lower Hutt. Fax: (04) 920 0873; email: stewart.reid@irl.cri.nz
References:
  1. Dow DA, Mansoor O. New Zealand immunisation schedule history. NZ Med J. 1996:109:209-12.
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