Pauline Waight

Herd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination in England and Wales: an observational cohort study

BACKGROUND The seven-valent pneumococcal conjugate vaccine (PCV7) has reduced vaccine-type (VT) invasive pneumococcal disease but increases in non-vaccine-type (NVT) disease have varied between countries. We assess the effect of the PCV7 vaccination on VT and NVT disease in England and Wales. METHODS The study cohort was the population of England and Wales from July, 2000, to June, 2010. We calculated incidence rate ratios (IRRs) to compare incidences of VT and NVT disease before (2000-06) and after (2009-10) the introduction of PCV7. We used data from the national surveillance database. Cases included in our analysis were restricted to those confirmed by culture linked with isolates referred for serotyping at the national reference centre by laboratories in England and Wales. We adjusted for potential bias from missing data (serotype and age of patient) and changes in case ascertainment rates during the study period. FINDINGS 5809 cases of invasive pneumococcal disease were reported in 2009-10, giving an incidence of 10·6 per 100,000 population in 2009-10, which, when compared with the adjusted average annual incidence of 16·1 in 2000-06, gives an overall reduction of 34% (95% CI 28-39). VT disease decreased in all age groups, with reductions of 98% in individuals younger than 2 years and 81% in those aged 65 years or older. NVT disease increased by 68% in individuals younger than 2 years and 48% in those aged 65 years or older, giving an overall reduction in invasive pneumococcal disease of 56% in those younger than 2 years and 19% in those aged 65 years or older. After vaccine introduction, more NVT serotypes increased in frequency than decreased, which is consistent with vaccine-induced replacement. Key serotypes showing replacement were 7F, 19A, and 22F. Increases in NVT invasive pneumococcal disease were not associated with antimicrobial resistance. INTERPRETATION Despite much serotype replacement, a substantial reduction in invasive pneumococcal disease in young children can be achieved with PCV7 vaccination, with some indirect benefit in older age groups. Further reductions should be achievable by use of higher valency vaccines. Robust surveillance data are needed to properly assess the epidemiological effect of multivalent pneumococcal disease vaccines. FUNDING Health Protection Agency.

Serotype-specific effectiveness and correlates of protection for the 13-valent pneumococcal conjugate vaccine: a postlicensure indirect cohort study.

BACKGROUND Efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13) was inferred before licensure from an aggregate correlate of protection established for the seven-valent vaccine (PCV7). We did a postlicensure assessment of serotype-specific vaccine effectiveness and immunogenicity in England, Wales, and Northern Ireland to derive the correlates of protection for individual serotypes. METHODS We assessed vaccine effectiveness against invasive pneumococcal disease using the indirect cohort method. We measured serotype-specific IgG concentration in infants after they were given two priming doses of PCV7 (n=126) or PCV13 (n=237) and opsonophagocytic antibody titre from a subset of these infants (n=100). We derived correlates of protection by relating percentage protection to a threshold antibody concentration achieved by an equivalent percentage of infants. We used multivariable logistic regression to estimate vaccine effectiveness and reverse cumulative distribution curves to estimate correlates of protection. FINDINGS For the 706 cases of invasive pneumococcal disease included in the study, PCV13 vaccine effectiveness after two doses before age 12 months or one dose from 12 months was 75% (95% CI 58-84). Vaccine effectiveness was 90% (34-98) for the PCV7 serotypes and 73% (55-84) for the six additional serotypes included in PCV13. Protection was shown for four of the six additional PCV13 serotypes (vaccine effectiveness for serotype 3 was not significant and no cases of serotype 5 infection occurred during the observation period). The vaccine effectiveness for PCV13 and PCV7 was lower than predicted by the aggregate correlate of protection of 0·35 μg/mL used during licensing. Calculated serotype-specific correlates of protection were higher than 0·35 μg/mL for serotypes 1, 3, 7F, 19A, 19F, and lower than 0·35 μg/mL for serotypes 6A, 6B, 18C, and 23F. Opsonophagocytic antibody titres of 1 in 8 or higher did not predict protection. INTERPRETATION PCV13 provides significant protection for most of the vaccine serotypes. Although use of the aggregate correlate of protection of 0·35 μg/mL has enabled the licensing of effective new PCVs, serotype-specific correlates of protection vary widely. The relation between IgG concentration after priming and long-term protection needs to be better understood. FUNDING Public Health England and UK Department of Health Research and Development Directorate.

Effect of pneumococcal conjugate vaccination on serotype-specific carriage and invasive disease in England: a cross-sectional study

A cross sectional study by Stefan Flasche and coworkers document the serotype replacement of Streptococcus pneumoniae that has occurred in England since the introduction of PCV7 vaccination.

Effectiveness of the new serotypes in the 13-valent pneumococcal conjugate vaccine

Efficacy of the new serotypes in the 13-valent pneumococcal conjugate vaccine (PCV13) against invasive pneumococcal disease (IPD) was based on a putative correlate of protection. In England and Wales, PCV13 replaced PCV7 in the 2, 4, and 13 month schedule in April 2010. Using non-vaccine type IPD cases as controls, we estimated vaccine effectiveness (VE) for the new serotypes. Among 166 IPD cases in PCV13 eligible children reported by July 2011 with known serotype and vaccination status, VE for 2 doses under a year was 78% (95% confidence interval -18% to 96%) and 77% (38-91%) for one dose over a year. VE for 7F and 19A was 76% (21-93%) and 70% (10-90%) respectively for ≥one dose. VE for serotypes 1 and 3 was 62% and 66% respectively although confidence intervals spanned zero. IPD due to PCV13-only serotypes halved in children under 2 years in the study period.

Idiopathic thrombocytopenic purpura and MMR vaccine

A CAUSAL ASSOCIATION BETWEEN MEASLES mumps–rubella (MMR) vaccine and idiopathic thrombocytopenic purpura (ITP) was confirmed using immunisation/hospital admission record linkage. The absolute risk within six weeks of immunisation was 1 in 22 300 doses, with two of every three cases occurring in the six week post-immunisation period being caused by MMR. Children with ITP before MMR had no vaccine associated recurrences.

Safety and immunogenicity of AS03B adjuvanted split virion versus non-adjuvanted whole virion H1N1 influenza vaccine in UK children aged 6 months-12 years: open label, randomised, parallel group, multicentre study.

Objectives To compare the safety, reactogenicity, and immunogenicity of an adjuvanted split virion H1N1 vaccine and a non-adjuvanted whole virion vaccine used in the pandemic immunisation programme in the United Kingdom. Design Open label, randomised, parallel group, phase II study. Setting Five UK centres (Oxford, Southampton, Bristol, Exeter, and London). Participants Children aged 6 months to less than 13 years for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures were eligible. Those with laboratory confirmed pandemic H1N1 influenza or clinically diagnosed disease meriting antiviral treatment, allergy to egg or any other vaccine components, or coagulation defects, or who were severely immunocompromised or had recently received blood products were excluded. Children were grouped by age: 6 months-<3 years (younger group) and 3-<13 years (older group). Recruitment was by media advertising and direct mailing. Recruitment visits were attended by 949 participants, of whom 943 were enrolled and 937 included in the per protocol analysis. Interventions Participants were randomised 1:1 to receive AS03B (tocopherol based oil in water emulsion) adjuvanted split virion vaccine derived from egg culture or non-adjuvanted whole virion vaccine derived from cell culture. Both were given as two doses 21 days apart. Reactogenicity data were collected for one week after immunisation by diary card. Serum samples were collected at baseline and after the second dose. Main outcome measures Primary reactogenicity end points were frequency and severity of fever, tenderness, swelling, and erythema after vaccination. Immunogenicity was measured by microneutralisation and haemagglutination inhibition assays. The primary immunogenicity objective was a comparison between vaccines of the percentage of participants showing seroconversion by the microneutralisation assay (fourfold rise to a titre of ≥1:40 from before vaccination to three weeks after the second dose). Results Seroconversion rates were higher after the adjuvanted split virion vaccine than after the whole virion vaccine, most notably in the youngest children (163 of 166 participants with paired serum samples (98.2%, 95% confidence interval 94.8% to 99.6%) v 157 of 196 (80.1%, 73.8% to 85.5%), P<0.001) in children under 3 years and 226 of 228 (99.1%, 96.9% to 99.9%) v 95.9%, 92.4% to 98.1%, P=0.03) in those over 3 years). The adjuvanted split virion vaccine was more reactogenic than the whole virion vaccine, with more frequent systemic reactions and severe local reactions in children aged over 5 years after dose one (13 (7.2%, 3.9% to 12%) v 2 (1.1%, 0.1% to 3.9%), P<0.001) and dose two (15 (8.5%, 4.8% to 13.7%) v 2 (1.1%, 0.1% to 4.1%), P<0.002) and after dose two in those under 5 years (15 (5.9%, 3.3% to 9.6%) v 0 (0.0%, 0% to 1.4%), P<0.001). Dose two of the adjuvanted split virion vaccine was more reactogenic than dose one, especially for fever ≥38ºC in those aged under 5 (24 (8.9%, 5.8% to 12.9%) v 57 (22.4%, 17.5% to 28.1%), P<0.001). Conclusions In this first direct comparison of an AS03B adjuvanted split virion versus whole virion non-adjuvanted H1N1 vaccine, the adjuvanted vaccine, while more reactogenic, was more immunogenic and, importantly, achieved high seroconversion rates in children aged less than 3 years. This indicates the potential for improved immunogenicity of influenza vaccines in this age group. Trial registration Clinical trials.gov NCT00980850; ISRCTN89141709.

Impact and effectiveness of 23-valent pneumococcal polysaccharide vaccine against invasive pneumococcal disease in the elderly in England and Wales.

In 2003 the existing 23-valent pneumococcal vaccine (PPV23) programme for high risk groups was extended to include all ≥ 65 year olds in England and Wales, starting with ≥ 80 year olds and moving to 75-79 and 65-74 year olds by 2005. We conducted an ecological study to assess the impact of the extended PPV23 programme on serotype-specific incidence of invasive pneumococcal disease (IPD) and a case-control study to assess vaccine effectiveness (VE) using the national IPD surveillance dataset. Between 1998 and 2006 IPD incidence caused by PPV23 serotypes in the targeted age-groups was unchanged. IPD caused by the serotypes covered by the 7-valent conjugate vaccine (PCV7) introduced for children in 2006 declined in ≥ 65 year olds after 2006 but was offset by an increase in non-PCV7 serotypes. This increase was similar for the additional 16 serotypes covered by PPV23 and the non-PPV23 serotypes. For the VE study, vaccine history was obtained for controls (n=1270) with non-PPV23 IPD diagnosed between November 2003 and December 2010 and a subset of cases (n=1272) matched for age and time period. VE declined from 48% (95% confidence interval; 32-60%) within two years of vaccination to 15% (-3% to 30%) after five years. Although differences in VE by age and having risk conditions were not statistically significant the highest estimates were in the youngest age group (65-74 years) and in those without risk conditions with a VE estimate of 65% (23-84%) within 2 years of vaccination for non-risk 65-74 year olds. VE differed by serotype (p=0.005), from -23% (-85% to 19%) for serotype 3 to 63% (29-81%) for 12F. In conclusion PPV23 was effective, particularly in healthy under 75 year olds, but protection waned after 5 years. There was no discernible impact of PPV23 on IPD incidence or PCV7-induced serotype replacement, consistent with the modest overall effectiveness, the 45% increased coverage over the former risk-based programme and lack of herd immunity from the PPV23 programme. Based on the VE estimates PPV23 was still considered a cost-effective intervention for the low risk elderly.

Invasive Pneumococcal Disease in England and Wales: Vaccination Implications

Knowledge of the epidemiology of invasive pneumococcal disease (IPD) will aid in planning the use of pneumococcal vaccines. A United Kingdom (UK)-based surveillance in England and Wales (1995-1997) of 11,528 individuals with IPD and a local enhanced surveillance in the Oxford (UK) area (1995-1999) have been analyzed. IPD has a high attack rate in children, with 37.1-48.1 cases per 100,000 infants <1 year old per year, and in older persons, with 21.2-36.2 cases per 100,000 persons >65 years old per year, for England, Wales, and Oxford. The 7-valent conjugate vaccine includes serotypes causing < or =79% of IPD in children <5 years old, but only 66% in adults >65 years old. The data also indicate that IPD varies by serotype, age, and country, emphasizing that the epidemiology of IPD is heterogeneous and requires continued surveillance.

The effect of underlying clinical conditions on the risk of developing invasive pneumococcal disease in England

OBJECTIVE To inform national policy making on the use of the 13-valent pneumococcal vaccine among risk groups we estimated the increased risk of invasive pneumococcal disease (IPD) outcomes among clinical risk groups. Three years of post 7-valent pneumococcal conjugate vaccine (PCV7) data was included to investigate the herd protection effects. METHODS Over 22,000 IPD patients in England (March 2002-March 2009 - aged 2 and over) were linked to their hospitalisation records. The prevalence of risk factors in these patients was compared to the prevalence of risk factors in the general population. RESULTS There was an increased odds ratio (OR) for hospitalisation (OR 11.7 2-15 years; 7.6 16-64; 2.7 65+) and death (OR 2.4 2-15 years, 3.9 16-64, 1.2 65+) from IPD among risk group. The most important risk factors that predict IPD are chronic liver disease, immunosuppression, and chronic respiratory diseases. Herd protection effects due to introduction of the 7-valent vaccine were identical in both patient groups as shown by the similar decline in the proportion of IPD caused by PCV7 serotypes in risk and non-risk groups. CONCLUSIONS There is a marked increased risk of IPD among those with certain clinical conditions, suggesting potential benefit from a targeted vaccination approach. However, the indirect protection from conjugate vaccination of children suggests PCV vaccination of high-risk groups may not provide substantial additional benefit once herd immunity takes effect.

Long-Term Protection against Carriage of Hepatitis B Virus after Infant Vaccination

BACKGROUND Carriage of hepatitis B virus (HBV) is a major risk factor for liver cirrhosis and hepatocellular carcinoma. Infant vaccination has been effective in preventing horizontal transmission during early childhood. It is unknown whether protection is maintained into early adulthood. METHODS In 1984, early childhood vaccination was introduced in 2 rural Gambian villages. In 2003, serological assessment of 81.5% of 1,350 eligible participants 1-24 years old was done, to determine vaccine efficacy against infection and carriage. RESULTS Overall vaccine efficacy against infection and carriage was 83.4% (95% confidence interval [CI], 79.8%-86.6%) and 96.5% (85% CI, 93.9%-98.9%), respectively. Vaccine efficacy against infection was similar when restricted to primary responders (85.3%), but a significant effect of peak antibody concentration was found. Both vaccine efficacy and levels of hepatitis B surface antibody (anti-HBs) decreased with age, resulting in a vaccine efficacy against infection and carriage among 20-24-year-old participants of 70.9% (95% CI, 60.4%-80.5%) and 91.1% (95% CI, 75.8%-100%), respectively. Fifteen years after vaccination, fewer than half of the vaccinees had detectable anti-HBs. The prevalence of carriage in the unvaccinated population was similar to the prevalence 20 years earlier. CONCLUSIONS HBV vaccination early during life can provide long-lasting protection against carriage, despite decreasing antibody levels. The role played by subclinical boosting and the necessity of a booster need to be evaluated.