Norman Begg

Meningococcal Serogroup C Conjugate Vaccine Is Immunogenic in Infancy and Primes for Memory

The safety, immunogenicity, and immunologic priming of 2 dosages (2 microgram or 10 microgram) of a meningococcal C oligosaccharide-CRM197 conjugate vaccine was evaluated in 114 infants vaccinated at ages 2, 3, and 4 months. Antibody persistence and response to boosting with 10 microgram of meningococcal C polysaccharide were assessed. The meningococcal conjugate vaccine produced fewer local reactions than concurrent routine immunizations. Total serogroup C-specific immunoglobulin geometric mean concentration (GMC) increased from 0.3 microgram/mL before vaccination to 13.1 microgram/mL at age 5 months. Serum bactericidal antibody (SBA) geometric mean titers (GMTs) rose from <1:4 to 1:1057 at 5 months and fell by 14 months to 1:19. Following boosting, anti-C-specific immunoglobulin GMC rose to 15.9 microgram/mL and SBA GMT to 1:495. Antibody responses in the 10-microgram dose cohort were significantly higher at 5 months (P<.01) than in the 2-microgram dose cohort but were lower after polysaccharide boosting (P=.02). This meningococcal conjugate vaccine was well tolerated and immunogenic and induced immunologic memory in infants.

Immunogenicity and reactogenicity in UK infants of a novel meningococcal vesicle vaccine containing multiple class 1 (PorA) outer membrane proteins.

The development of effective vaccines against serogroup B meningococci is of great public health importance. We assessed a novel genetically engineered vaccine containing six meningococcal class 1 (PorA) outer membrane proteins representing 80% of prevalent strains in the UK. 103 infants were given the meningococcal vaccine at ages 2, 3 and 4 months with routine infant immunisations, with a fourth dose at 12-18 months. The vaccine was well tolerated. Three doses evoked good immune responses to two of six meningococcal strains expressing PorA proteins contained in the vaccine. Following a fourth dose, larger bactericidal responses to all six strains were observed, suggesting that the initial course had primed memory lymphocytes and revaccination stimulated a booster response. This hexavalent PorA meningococcal vaccine was safe and evoked encouraging immune responses in infants. Vaccines of this type warrant further development and evaluation.

Vaccine failures after primary immunisation with Haemophilus influenzae type-b conjugate vaccine without booster

BACKGROUND Diseases of early childhood associated with Haemophilus influenzae type b (Hib) can now be prevented by vaccination. The rapid implementation of routine infant vaccination with Hib polysaccharide-tetanus protein conjugate (PRP-T) vaccine has allowed us to assess whether an accelerated 2, 3, and 4 month schedule can protect in the longer term without a booster dose and whether carrier priming influences protective efficacy. The degree of protection afforded by a catch-up programme with Hib oligosaccharide conjugate (HbOC) for older children was also assessed. METHODS Paediatricians and microbiologists in the UK were asked to report all cases of invasive H influenzae infection in children who had received at least one dose of Hib-conjugate vaccine. Serum samples from convalescent children were obtained and the isolate was verified. Efficacy was estimated by comparing observed rates of Hib disease in those who had been vaccinated with rates predicted by age adjustment of disease rates from the prevaccine era. FINDINGS Of 164 reports of invasive infection between Oct 1, 1992, and Oct 1, 1995, 43 were considered true vaccine failures. The estimated overall efficacy for three doses of PRP-T was 98.1% (95% CI 97.3-98.7%). Efficacy in infants aged 5-11 months was 99.1%, 12-23 months 97.3%, and 24-35 months 94.7%. In infants aged 3-11 months, who received their first dose of PRP-T after tetanus toxoid vaccination, disease was unlikely from 1 week after one dose of PRP-T vaccine (88.6% protection in the second to fourth weeks [66.8-97.7%]). The disease rate in vaccinated infants aged 2 months has declined year on year. In children aged 13 months to 2 years given HbOC, as a catch-up vaccine, the estimated efficacy was 94.0% (84.7-98.4%). INTERPRETATION A high degree of efficacy has been observed with PRP-T vaccine given as a three-dose schedule in infancy and with HbOC as a single dose in older children. Efficacy of PRP-T appears to be enhanced by carrier priming. Although with increasing age there was a small decline in efficacy of PRP-T, Hib disease is now close to being eliminated in the UK, and we suggest that a booster is not necessary in the second year of life.

Induction of immunological memory in UK infants by a meningococcal A/C conjugate vaccine

The induction of immunological memory to serogroup A and C polysaccharides in UK infants immunized with three doses of a meningococcal A/C oligosaccharide CRM197 conjugate vaccine was investigated. Forty UK infants vaccinated previously with three doses of a meningococcal A/C oligosaccharide-CRM197 conjugate vaccine at 2, 3 and 4 months of age, were revaccinated at a mean age of 145.6 weeks with either a 10 or 50 microg dose of licensed meningococcal A/C polysaccharide vaccine. Serogroup-specific antibody and serum bactericidal antibody (SBA) responses were measured by enzyme-linked immunosorbent assay and serum bactericidal assays, respectively. Following challenge, anti-serogroup A and C polysaccharide antibody levels rose from pre-booster geometric mean concentrations (GMC) of 3.1 and 2.1 microg/ml respectively to 19.6 and 21.0 microg/ml 1 month post-booster. Serum bactericidal antibody geometric mean titres (GMTs) for serogroups A and C increased 156- and 113-fold from 2.1 and 7.1 pre-booster respectively to 327.4 and 800.7 post-booster. A serogroup A control group of 45 children received a 10 microg dose of licensed meningococcal A/C polysaccharide vaccine (with no prior history of serogroup A vaccination) had serogroup A SBA GMTs of 2.3 pre-vaccination rising to 8 post-vaccination with corresponding GMCs of 0.8 and 10.8 microg/ml. These rises in SBA following serogroup A/C conjugate vaccination are indicative of immunological priming.

Paralytic poliomyelitis in England and Wales, 1985-91.

OBJECTIVES--To ascertain all cases of paralytic poliomyelitis in England and Wales during 1985-91 and to determine the source of infection in each case. DESIGN--Descriptive study of cases reported between 1985 and 1991. SETTING--All health districts in England and Wales. SUBJECTS--Patients normally resident in England and Wales whose clinical features were consistent with paralytic poliomyelitis or with laboratory evidence of recent poliovirus infection and compatible symptoms. MAIN OUTCOME MEASURES--Clinical, epidemiological, and laboratory features in identified cases. RESULTS--Of 54 suspected cases of poliomyelitis, 33 were excluded, leaving 21 cases, of which 13 were vaccine associated (nine recipient and four contact) cases, five were imported cases, and three were cases whose source of infection was unknown. No cases due to indigenous wild polioviruses were identified; two were imported cases due to wild viruses. One patient died during the acute phase of the illness, and two children with previously unrecognised severe congenital immune deficiency died between one and two months after the onset of paralysis after the first or second dose of oral polio vaccine. The estimated risk of vaccine associated paralysis is 1.46 per million for the first dose, 0.49 for the second, zero for the third and fourth doses, and 0.33 for the fifth. CONCLUSIONS--Indigenous wild poliovirus seems to have been eradicated, although wild virus may be imported; improved surveillance of suspected cases including immediate notification and characterisation of the virus to ensure that eradication is maintained is essential.

Role of epidemiology in vaccine policy

The application of epidemiological techniques is important at all stages in the development of a vaccination programme. Before licensing, the safety and efficacy of a new vaccine must be determined in carefully designed clinical trials. An epidemiological assessment of the disease is then needed in order to formulate an appropriate strategy for delivery of the vaccine. Once the vaccine has been introduced into routine use, continued evaluation, both of the vaccine and the programme, is required. Surveillance schemes should be established that are capable of detecting changes in vaccine safety and efficacy as well as monitoring coverage in the target population. Any important changes should be further evaluated by special studies. Postlicensing evaluation of vaccines and vaccination programmes has played an important role in shaping policy in the UK.

Antibody response and viral excretion after live polio vaccine or a combined schedule of live and inactivated polio vaccines.

A randomized controlled trial was performed in infants undergoing routine immunization in North Hertfordshire. Ninety-six children received a single dose of inactivated polio vaccine, followed by two doses of live attenuated oral polio vaccine and 97 children received three doses of live attenuated oral polio vaccine at 2, 3 and 4 months of age. Blood samples were taken by study nurses 6 weeks after vaccination and stool samples were collected by parents weekly for 4 weeks after each dose of vaccine. Follow-up was completed for 92 of 96 (96%) children in the combined schedule group and 92 of 97 (95%) in the control group. After vaccination the proportions of children with detectable antibody to poliovirus serotypes 1, 2 and 3 were high and similar between groups and geometric mean titers (95% confidence interval) to poliovirus types 1, 2 and 3 were 264 (200 to 347), 375 (311 to 450) and 189 (144 to 250) in the combined schedule group and 369 (290 to 469), 401 (321 to 498) and 206 (145 to 293) in the live vaccine group, respectively. The only significant difference between groups in rates of viral excretion was observed after the second dose of live attenuated oral polio vaccine, when excretion of type 3 poliovirus was reduced in those children who had received prior inactivated polio vaccine (P = 0.05). This study suggests that, compared with the current schedule, a combined schedule of inactivated and live poliovaccines is likely to produce equivalent individual protection against poliomyelitis and is unlikely to substantially alter circulation of poliovirus in the community.(ABSTRACT TRUNCATED AT 250 WORDS)

Salivary antibodies following parenteral immunization of infants with a meningococcal serogroup A and C conjugated vaccine.

Bacterial and viral salivary antibody testing is proving sensitive and specific, useful for epidemiological studies, and is simple and non-invasive. Salivary serogroup C polysaccharide-specific (SC PS-S) IgA and IgG were determined as a proportion of total salivary IgA and IgG in a group of UK infants who were recipients of a conjugated A/C meningococcal PS vaccine. Geometric mean concentrations (GMCs) of salivary SC PS-S IgG per mg of total IgG (microg/mg) were 0.1 pre-vaccination, rising to 8.2 post first, 16.1 post second and 29.3 post third dose of vaccine. For IgA, the corresponding GMCs in ng/mg were 0.1, 82.8, 69.6 and 91.2. Significant correlations (P < 0.0001) were found between serum Ig and salivary IgG SC PS-S antibody for pre-vaccine and 1 month post each dose of vaccine suggesting that SC PS-S IgG in saliva was largely derived from serum. Of the five infants whose sera were analysed for isotype-specific responses, only traces of IgM and IgA were measurable suggesting that the SC PS-S IgA was locally produced. These findings suggests that the widespread use of meningococcal conjugate vaccines is likely to reduce nasopharyngeal carriage and may thereby induce herd immunity in the vaccinated population.

Antibody responses and symptoms after DTP and either tetanus or diphtheria Haemophilus influenzae type B conjugate vaccines given for primary immunisation by separate or mixed injection

The safety and immunogenicity of two conjugate Haemophilus influenzae type B (Hib) vaccines administered either mixed with, or in separate limbs to, a whole-cell DTP vaccine, was compared in infants vaccinated at 2, 3 and 4 months of age. Antibody titres to purified polyribosylribitol phosphate, diphtheria, and to pertussis antigens between infants who received the Hib and DPT vaccines in separate limbs or in the same limbs were similar (P > 0.1) while antibody titres to tetanus toxoid were higher in the later group (P < 0.05). This study demonstrated that both Hib vaccines can be mixed with whole-cell DTP vaccine without reducing immunogenicity of either vaccine or increasing the incidence of adverse reactions.

Meningococcal disease and healthcare workers.

Although Neisseria meningitidis is a relatively uncommon cause of overt infection (2580 notifications in 1998),1 the horrors of its clinical presentation have stimulated intense media interest, particularly after outbreaks. With the disappearance of many infectious competitors in the latter half of this century, meningococcal disease has become the leading infectious cause of death in childhood and is now the third most common cause of death in children outside infancy (after accidents and malignancy).2 The introduction in October 1999 of a serogroup C protein-polysaccharide conjugate vaccine for children and young adults has the potential to reduce significantly the incidence of disease.3 Nevertheless, most cases are caused by serogroup B meningococci, for which no vaccine is available, and the disease will remain prevalent in the United Kingdom. As a result of the dramatic presentation of cases and the high fatality rate the perceived risk of meningococcal disease is high among those who have had …