Lode Schuerman

Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: a randomised double-blind efficacy study

Summary Background Acute otitis media is one of the most commonly-diagnosed childhood infections. This study assessed the efficacy of a novel vaccine that contained polysaccharides from 11 different Streptococcus pneumoniae serotypes each conjugated to Haemophilus influenzae -derived protein D in prevention of acute otitis media. Methods 4968 infants were randomly assigned to receive either pneumococcal protein D conjugate or hepatitis A vaccine at the ages of 3, 4, 5, and 12–15 months and were followed-up until the end of the second year of life. Middle-ear fluid was obtained for bacteriological culture and serotyping in children who presented with abnormal tympanic membrane or presence of middle-ear effusion, plus two predefined clinical symptoms. The primary endpoint was protective efficacy against the first episode of acute otitis media caused by vaccine pneumococcal serotypes. Analysis was per protocol. Findings From 2 weeks after the third dose to 24–27 months of age, 333 clinical episodes of acute otitis media were recorded in the protein D conjugate group (n=2455) and 499 in the control group (n=2452), giving a significant (33·6% [95% CI 20·8–44·3]) reduction in the overall incidence of acute otitis media. Vaccine efficacy was shown for episodes of acute otitis media caused by pneumococcal vaccine serotypes (52·6% [35·0–65·5] for the first episode and 57·6% [41·4–69·3] for any episode). Efficacy was also shown against episodes of acute otitis media caused by non-typable H influenzae (35·3% [1·8–57·4]). The vaccine reduced frequency of infection from vaccine-related cross-reactive pneumococcal serotypes by 65·5%, but did not significantly change the number of episodes caused by other non-vaccine serotypes. Interpretation These results confirm that using the H influenzae -derived protein D as a carrier protein for pneumococcal polysaccharides not only allowed protection against pneumococcal otitis, but also against acute otitis media due to non-typable H influenzae . Whether this approach would also allow improved protection against lower respiratory tract infections warrants further investigation.

Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials

BACKGROUND Although fever is part of the normal inflammatory process after immunisation, prophylactic antipyretic drugs are sometimes recommended to allay concerns of high fever and febrile convulsion. We assessed the effect of prophylactic administration of paracetamol at vaccination on infant febrile reaction rates and vaccine responses. METHODS In two consecutive (primary and booster) randomised, controlled, open-label vaccination studies, 459 healthy infants were enrolled from ten centres in the Czech Republic. Infants were randomly assigned with a computer-generated randomisation list to receive three prophylactic paracetamol doses every 6-8 h in the first 24 h (n=226) or no prophylactic paracetamol (n=233) after each vaccination with a ten-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) co-administered with the hexavalent diphtheria-tetanus-3-component acellular pertussis-hepatitis B-inactivated poliovirus types 1, 2, and 3-H influenzae type b (DTPa-HBV-IPV/Hib) and oral human rotavirus vaccines. The primary objective in both studies was the reduction in febrile reactions of 38.0 degrees C or greater in the total vaccinated cohort. The second objective was assessment of immunogenicity in the according-to-protocol cohort. These studies are registered with ClinicalTrials.gov, numbers NCT00370318 and NCT00496015. FINDINGS Fever greater than 39.5 degrees C was uncommon in both groups (after primary: one of 226 participants [<1%] in prophylactic paracetamol group vs three of 233 [1%] in no prophylactic paracetamol group; after booster: three of 178 [2%] vs two of 172 [1%]). The percentage of children with temperature of 38 degrees C or greater after at least one dose was significantly lower in the prophylactic paracetamol group (94/226 [42%] after primary vaccination and 64/178 [36%] after booster vaccination) than in the no prophylactic paracetamol group (154/233 [66%] after primary vaccination and 100/172 [58%] after booster vaccination). Antibody geometric mean concentrations (GMCs) were significantly lower in the prophylactic paracetamol group than in the no prophylactic paracetamol group after primary vaccination for all ten pneumococcal vaccine serotypes, protein D, antipolyribosyl-ribitol phosphate, antidiphtheria, antitetanus, and antipertactin. After boosting, lower antibody GMCs persisted in the prophylactic paracetamol group for antitetanus, protein D, and all pneumococcal serotypes apart from 19F. INTERPRETATION Although febrile reactions significantly decreased, prophylactic administration of antipyretic drugs at the time of vaccination should not be routinely recommended since antibody responses to several vaccine antigens were reduced. FUNDING GlaxoSmithKline Biologicals (Belgium).

Immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) compared to the licensed 7vCRM vaccine

Background: The immunogenicity of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) was assessed and compared with the 7-valent pneumococcal conjugate vaccine (7vCRM). Methods: Healthy subjects (1650) were randomized to be vaccinated with 3 doses of PHiD-CV or 7vCRM (Prevenar™/Prevnar™) at 2-3-4 months of age and a fourth booster dose at 12–18 months. Serotype-specific pneumococcal responses (GlaxoSmithKlines ELISA with 22F-inhibition) and opsonophagocytic activity (OPA) were measured 1 month after primary and booster vaccinations. Results: The primary objective to demonstrate noninferiority of PHiD-CV versus 7vCRM (in terms of percentage of subjects with antibody concentration ≥0.2 &mgr;g/mL) for at least 7 of the 10 vaccine serotypes was reached as noninferiority was demonstrated for 8 serotypes. Although, noninferiority could not be demonstrated for ELISA responses against serotypes 6B and 23F, a post-hoc analysis of the percentage of subjects with OPA titers ≥8 suggested noninferiority for the 7 serotypes common to both vaccines including 6B and 23F. Priming of the immune system against all vaccine serotypes was confirmed by robust increases in ELISA antibody levels (∼6.0–17 fold) and OPA titers (∼8–93 fold) after a fourth consecutive dose of PHiD-CV. Conclusions: PHiD-CV induces ELISA and functional OPA antibodies for all vaccine serotypes after primary vaccination and is noninferior to 7vCRM in terms of ELISA and/or OPA threshold responses. Effective priming is further indicated by robust booster responses.

Effectiveness of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against invasive pneumococcal disease: a cluster randomised trial

BACKGROUND The Finnish Invasive Pneumococcal disease (FinIP) vaccine trial was designed to assess the effectiveness of a pneumococcal vaccine containing ten serotype-specific polysaccharides conjugated to Haemophilus influenzae protein D, tetanus toxoid, and diphtheria toxoid as the carrier proteins (PHiD-CV10) against invasive pneumococcal disease. METHODS In this cluster-randomised, double-blind trial, children aged younger than 19 months received PHiD-CV10 in 52 clusters or hepatitis vaccines as control in 26 clusters. Infants aged younger than 7 months at the first vaccination received either a 3+1 or a 2+1 vaccination schedule, children aged 7-11 months received a 2+1 schedule, and those 12-18 months of age received a two-dose schedule. The primary and secondary objectives were to assess vaccine effectiveness against culture-confirmed invasive pneumococcal disease due to any of the ten vaccine serotypes for the 3+1 and 2+1 schedules, respectively, in children who received at least one PHiD-CV10 dose before 7 months of age. Masked follow-up of pneumococcal disease lasted from the first vaccination (from February, 2009, to October, 2010) to January 31, 2012. Invasive disease data were retrieved from data accumulated in the national infectious diseases register. This trial and the nested acute otitis media trial are registered with ClinicalTrials.gov, numbers NCT00861380 and NCT00839254, respectively. FINDINGS 47,369 children were enrolled from February, 2009, to October, 2010. 30,528 participants were assessed for the primary objective. 13 culture-confirmed vaccine-type cases of invasive pneumococcal disease were detected: none in the PHiD-CV10 3+1 group, one in the PHiD-CV10 2+1 group, and 12 in the control groups. The estimates for vaccine effectiveness were 100% (95% CI 83-100) for PHiD-CV10 3+1 and 92% (58-100) for PHiD-CV10 2+1 groups. Two cases of any culture-confirmed invasive disease irrespective of serotype were detected in combined PHiD-CV10 infant cohorts compared with 14 in the corresponding control cohorts (vaccine effectiveness 93%, 75-99). In catch-up cohorts, seven cases of invasive disease were reported, all in the control group: two cases in the children enrolled at 7-11 months of age; and five cases in children enrolled at 12-18 months of age (vaccine effectiveness 100%, 79-100). Non-fatal serious adverse events suspected to be vaccine-related were reported via routine post-immunisation safety surveillance in 18 children. INTERPRETATION This nationwide trial showed high PHiD-CV10 effectiveness against invasive pneumococcal disease when given in different schedules. For the first time, effectiveness of a 2+1 schedule in infants was confirmed in a clinical trial. FUNDING GlaxoSmithKline Biologicals SA and National Institute for Health and Welfare, Finland.

10-valent pneumococcal nontypeable Haemophilus influenzae PD conjugate vaccine: Synflorix™

The global burden of disease due to Streptococcus pneumoniae remains high. The licensed 7-valent pneumococcal conjugate vaccine (7vCRM, Prevenar™/Prevnar™) has successfully reduced invasive disease in the USA, but serotype coverage is incomplete and some evidence suggests that serotype replacement has occurred. Recently, a new 10-valent pneumococcal nontypeable Haemophilus influenzae (NTHi) protein D (PD) conjugate vaccine (PHiD-CV, Synflorix™) has been licensed in more than 40 countries, including Europe, for the prevention of invasive disease and acute otitis media (AOM) due to pneumococcus in infants and children. PHiD-CV is immunogenic in infants when administered as a three-dose primary vaccination in a range of schedules and has a safety profile comparable to that of 7vCRM. Additional serotypes in PHiD-CV (1, 5 and 7F) increase overall serotype coverage and improve coverage in specific age groups and against specific disease syndromes. The use of the PD carrier, which provided protection against AOM caused by NTHi in a large efficacy trial testing a prototype of the final vaccine formulation, suggests that PHiD-CV will also provide some protection against AOM due to NTHi.

Effects of the 10-Valent Pneumococcal Nontypeable Haemophilus influenzae Protein D-Conjugate Vaccine on Nasopharyngeal Bacterial Colonization in Young Children: A Randomized Controlled Trial

This study evaluated effects of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D-conjugate vaccine (PHiDCV) compared with the 7-valent vaccine on nasopharyngeal bacterial colonization, specifically nontypeable Haemophilus influenzae (NTHi). PHiD-CV had no differential effect on nasopharyngeal NTHi colonization.

Effect of vaccination with pneumococcal capsular polysaccharides conjugated to Haemophilus influenzae-derived protein D on nasopharyngeal carriage of Streptococcus pneumoniae and H. influenzae in children under 2 years of age.

Following primary and booster vaccination with an 11-valent pneumococcall protein D conjugate vaccine there was a 42.8% (95% CI: -16.7 to 71.9, ns) reduction in the carriage of Streptococcus pneumoniae vaccine serotypes and a 42.6% (95% CI: 1.3-66.6) reduction in the carriage of Haemophilus influenzae identified by standard microbiological techniques. When PCR and immunoblot assays were used to further improve specificity of non-typeable H. influenzae strain identification, carriage of H. influenzae was still reduced with 38.6% (95% CI: -6.3 to 64.6, ns). Reduction of acute otitis media (AOM) episodes preceded the impact on carriage. These data provide further support of the functional role of the protein D immunity.

Immunity to pertussis 5 years after booster immunization during adolescence.

BACKGROUND We conducted a 5-year follow-up study on the persistence of pertussis-specific antibody and cell-mediated immunity after booster immunization of adolescents aged 11-13 years with a tricomponent acellular pertussis vaccine (Boostrix; trials diphtheria-tetanus-acellular pertussis [Tdap]-004/030). METHODS Cellular and humoral immunity to pertussis toxin (PT), filamentous hemagglutinin, and pertactin were measured in adolescents (age, 16 years) 5 years after booster immunization. Similar investigations were performed for control adolescents who had received only diphtheria and tetanus booster vaccination. RESULTS Five years after pertussis booster vaccination, the geometric mean concentrations of immunoglobulin G (IgG) elicited by each of the 3 pertussis vaccine antigens decreased from 1-month and 3-year postvaccination levels, but with the exception of PT IgG, were still higher than the prevaccination levels. PT IgG levels were undetectable in 28% of the subjects, but 44% of those subjects still tested positive for cell-mediated immunity to PT. Filamentous hemagglutinin IgG and pertactin IgG levels were significantly higher in Tdap-boosted adolescents than in the control subjects. Antibody concentrations at 1 month after vaccination strongly predicted antibody persistence. Cell-mediated immunity levels to PT, filamentous hemagglutinin, and pertactin persisted above the prebooster levels measured 5 years earlier. CONCLUSIONS The results of the present study of adolescents indicate that the interval between acellular pertussis booster immunizations might be extended beyond 5 years.

Immunogenicity and reactogenicity of four doses of diphtheria-tetanus-three-component acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b vaccine coadministered with 7-valent pneumococcal conjugate Vaccine.

Background: The 7-valent pneumococcal (7vPn) conjugate vaccine is licensed for primary and booster vaccination according to the same immunization schedules as routinely recommended diphtheria-tetanus-pertussis-based childhood vaccines and can be coadministered during the same vaccination visit. Methods: An open, randomized study evaluated the immunogenicity and safety of a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b (DTPa-HBV-IPV/Hib) vaccine and a 7vPn conjugate vaccine when coadministered at 2, 3 and 4 months and 12–23 months of age, compared with the administration of the hexavalent DTPa-HBV-IPV/Hib vaccine given alone. Serum antibody titers were measured before and 1 month after the primary course and before and 1 month after the booster dose. Solicited local and general adverse events were recorded for 4 days and unsolicited adverse events were recorded for 30 days after each vaccine dose. Results: A total of 345 subjects were enrolled for primary vaccination with the hexavalent vaccine (170 without and 175 with the 7vPn vaccine coadministered) and 266 returned for booster vaccination (122 without and 144 with coadministration of the 7vPn vaccine). After primary vaccination, antibody responses against the common antigens were similar in both groups, with seroprotection rates of 93.6–100% and with similar antibody decay before booster vaccination. The fourth dose induced a vigorous booster response, with seroprotection/vaccine response rates of 96.8–100%. Response to the 7vPn primary and booster vaccination was within previously reported ranges. Differences in reactogenicity resulted from higher incidences of symptoms after concomitant vaccination. Rectal temperature >39.5°C was observed after 1.2% of the coadministered vaccine doses during primary vaccination and after 2.8% of the booster vaccine doses. Conclusion: Coadministration of the DTPa-HBV-IPV/Hib and 7vPn vaccines at separate injection sites during the same vaccination visit was effective and safe.

Immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) when coadministered with different Neisseria meningitidis serogroup C conjugate vaccines.

Background: Immunogenicity of the candidate 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) was assessed when coadministered with other routine pediatric vaccines including different Neisseria meningitidis serogroup C conjugate vaccines. Methods: One thousand five hundred forty-eight healthy infants received, according to a balanced (1:1:1:1) randomization, either PHiD-CV coadministered with (1) DTPa-HBV-IPV/Hib (Infanrix hexa™) and MenC-CRM (Meningitec™), (2) DTPa-HBV-IPV/Hib and MenC-TT (NeisVac-C™), or (3) DTPa-HBV-IPV (Infanrix penta™/Pediarix™) and Hib-MenC-TT (Menitorix™); or 7vCRM (Prevenar™/Prevnar™) coadministered with DTPa-HBV-IPV and Hib-MenC-TT at 2-4-6 months of age with a booster dose at 11–18 months. Serotype-specific pneumococcal responses were measured by 22F-inhibition ELISA and opsonophagocytic (OPA) assay. Results: In all 3 coadministration groups, PHiD-CV was immunogenic for each of the 10 pneumococcal vaccine serotypes as assessed by post-primary and post-booster antibody ELISA and OPA responses. When coadministered with DTPa-HBV-IPV, Hib, and MenC antigens, PHiD-CV responses after the third primary dose were within the same range as 7vCRM responses in terms of the percentage of subjects achieving an ELISA antibody concentration ≥0.2 &mgr;g/mL for all common vaccine serotypes (over 92% of subjects) except for serotype 6B (at least 87% of subjects). ELISA and OPA immune responses were also evident after the second primary doses of PHiD-CV or 7vCRM vaccine, although antibody levels were below that achieved after 3 primary doses, particularly for serotypes 6B and 23F. The kinetics of the immune responses from after the second dose to after the booster dose were similar for most of the serotypes in both PHiD-CV and 7vCRM groups. Conclusions: PHiD-CV was immunogenic when coadministered with other routine pediatric vaccines including MenC conjugate vaccines.