ABSTRACT We compared the abilities of two serological readouts, antipolysaccharide IgG antibody concentrations and opsonophagocytic activity (OPA) titers, to predict the clinical effectiveness of the 7-valent pneumococcal conjugate vaccine (7vCRM) against invasive pneumococcal disease (IPD). We also assessed the accuracy of the previously established thresholds for GlaxoSmithKline's enzyme-linked immunosorbent assay with 22F adsorption (22F-ELISA) (≥0.2 μg/ml) and OPA assay (titer, ≥8) in predicting effectiveness. We showed that following a 3-dose 7vCRM primary vaccination, the serological response rates as determined using thresholds of ≥0.2 μg/ml IgG and an OPA titer of ≥8 corresponded well with overall effectiveness against IPD. In addition, the OPA assay seemed to better predict serotype-specific effectiveness than enzyme-linked immunoassay. Finally, when applied to post-dose-2 immune responses, both thresholds also corresponded well with the overall IPD effectiveness following a 2-dose 7vCRM primary vaccination. These results support the importance of the OPA assay in evaluating immune responses to pneumococcal conjugate vaccines.

Meningococcal disease incidence is highest in young children, yet a tetravalent conjugate vaccine is currently not available for this age group. This study evaluated a single dose of four different ACWY-TT conjugate vaccine formulations in 240 toddlers (12-14 months) and 268 children (3-5 years) compared to licensed age-appropriate control vaccines. In toddlers, rSBA-MenC GMTs for the selected formulation were statistically higher than after monovalent-MenC-conjugate vaccine. In children, rSBA-GMTs against each serogroup were statistically higher than after tetravalent polysaccharide vaccine. The safety profile was comparable to licensed controls. The new ACWY-TT conjugate vaccine promises high seroprotection levels against meningococcal disease from 1 year of age.

Objective: To assess immunogenicity, antibody persistence, immune memory, and reactogenicity of a novel heptavalent DTPw-HBV/Hib-MenAC (diphtheria, tetanus, whole cell pertussis-hepatitis B virus/Haemophilus influenzae type b-Neisseria meningitidis serogroups A and C) vaccine.Design: This was an open, randomized study in the Philippines, with DTPw-HBV/Hib-MenAC administered at 6, 10, and 14 weeks of age. Three different polysaccharide contents of the conjugate vaccine components Were assessed with conjugated PRP (potyribosytribitol phosphate), MenA, and MenC polysaccharides at the following doses: 2.5 mu g of each, 5 mu g of each, or 2.5 mu g of PRP and 5 mu g each of MenA and MenC. Controls received licensed DTPw-HBV and Hib or DTPw-HBV/Hib and MenC conjugate vaccines separately. Immune memory was evaluated via plain polysaccharide challenge administered to half of the subjects at 10 months of age.Results: After primary vaccination, at least 97.7% of DTPw-HBV/Hib-MenAC recipients had serum bactericidal antibody (SBA)-MenA and SBA-MenC titers >1:8, and at least 99% had anti-PRP antibody concentrations >= 0.151 mu g/ml. Immune responses to DTPw-HBV components were not impaired by the lowest dose of Hib-MenAC vaccine. Plain polysaccharide challenge induced marked increases in Hib, MenA, and MenC antibodies in primed subjects, indicative of immune memory. All of the experimental vaccines were well tolerated.Conclusion: The lowest dose of DTPw-HBV/Hib-MenAC polysaccharide conjugate vaccine was well tolerated, immunogenic, had good persistence of antibodies, and demonstrated immune memory, and consequently was selected for further development. (C) 2008 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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.

In Portugal, Neisseria meningitidis serogroup B (MenB) is the most common serogroup causing invasive meningococcal disease. To protect against MenB disease two protein based MenB vaccines are available in Portugal, the 4CMenB that was licenced in 2014 and included in the routine immunization program in October 2020, and the bivalent rLP2086 vaccine licensed in 2017. The aim of this study was to predict the coverage of the 4CMenB and rLP2086 vaccines against Portuguese isolates of Neisseria meningitidis sampled between 2012 and 2019 and to evaluate the diversity of vaccine antigens based on genomic analysis.Whole-genome sequence data from 324 Portuguese Neisseria meningitidis isolates were analysed. To predict strain coverage by 4CMenB and rLP2086, vaccine antigen reactivity was assessed using the MenDeVar index available on the PubMLST Neisseria website.This study included 235 (75.6%) MenB isolates of all invasive MenB strains reported between 2012 and 2019. Moreover, 89 non MenB isolates sampled in the same period, enrolling 68 from invasive disease and 21 from healthy carriers, were also studied.The predicted strain coverage of MenB isolates was 73.5% (95% CI: 64.8%–81.2%) for 4CMenB and 100% for rLP2086. Predicted strain coverage by 4CMenB in the age group from 0 to 4 years old, was 73.9%. Most of MenB isolates were covered by a single antigen (85.4%), namely fHbp (30.3%), P1.4 (29.2%), and NHBA (24.7%).In Portugal, the most prevalent peptides in MenB isolates were: P1.4 (16.2%), NHBA peptide 2 (14.0%), and fHbp peptide 14 (7.2%), from 4CMenB and fHbp peptide 19 (10.6%) from rLP2086. No significant temporal trends were observed concerning the distribution and diversity of vaccine antigen variants.4CMenB and rLP2086 vaccines showed potential coverage for isolates regardless serogroup.The use of both vaccines should be considered to control possible outbreaks caused by serogroups with no vaccine available.

ABSTRACT An experimental bivalent meningococcal outer membrane vesicle (OMV) vaccine (B:4:P1.19,15 and B:4:P1.7-2,4) has been developed to provide wide vaccine coverage particularly of the circulating strains in Europe. A randomized, controlled phase II study (study identification number, 710158/002; ClinicalTrials.gov identifier number, NCT00137917) to evaluate the immunogenicity and safety of three doses of the OMV vaccine when given to healthy 12- to 18-year-olds on a 0-2-4 month (n = 162) or 0-1-6 month schedule (n = 159). A control group received two doses of hepatitis A and one of conjugated meningococcal serogroup C vaccine on a 0-1-6 month schedule (n = 157). Immune response, defined as a fourfold increase in serum bactericidal titer using a range of vaccine-homologous or PorA-related and heterologous strains, was determined for samples taken before and 1 month after vaccination; assays were performed at two laboratories. As measured at the GlaxoSmithKline (GSK) laboratory, the OMV vaccine induced an immune response against homologous or PorA-related strains (in at least 51% of subjects against strains of serosubtype P1.19,15 and at least 66% against strains of serosubtype P1.7-2,4) and against a set of three heterologous strains (in 28% to 46% of subjects). Both laboratories showed consistent results for immune response rates. The OMV vaccine had a similar reactogenicity profile for each schedule. Pain preventing normal activities occurred in approximately one-fifth of the subjects; this was significantly higher than in the control group. The immune responses induced by the bivalent OMV vaccine demonstrated the induction of bactericidal antibodies against the vaccine-homologous/PorA-related strains but also against heterologous strains, indicating the presence of protective antigens in OMVs and confirming the potential of clinical cross-protection.

During a randomised controlled trial with the 23-valent pneumococcal vaccine in older persons, antibody concentrations and opsonophagocytic activity (OPA) were compared between eight patients who developed culture-verified pneumococcal pneumonia and 38 controls, matched for age, sex and vaccination status. Patients who developed pneumococcal pneumonia did not respond with a significant increase of antibody concentration (>1microg/ml) post-vaccination to the infecting serotype, but responded equally well as controls to most other serotypes. Neither was there any significant difference in the OPA post-vaccination between patients and controls. In conclusion, the 23-valent pneumococcal vaccine should be regarded as 23 different vaccines, rather than one. Older persons who fail to respond to one serotype may well be protected against infection by the other 22 serotypes.

A significant increase in the incidence of pertussis in adolescents and adults has been observed in vaccinated populations. Concomitantly, emergence of novel pertussis toxin and pertactin types in circulating Bordetella pertussis isolates was noticed. In this study, immunity induced by acellular vaccines against infection due to isolates expressing different pertactin types and fimbriae was monitored in a mouse model. In accordance with previous studies, the effect of a bicomponent DTPa vaccine on bacterial clearance was lower when compared with tri- or pentavalent DTPa vaccines. Whatever the isolates used to infect mice, the tri- or pentavalent DTPa vaccines were both efficacious in inducing immunity that resulted in clearance of infection. These findings suggest that re-emergence of pertussis might not be related to emergence of isolates escaping vaccine protection. The present study reduces potential concerns about acellular vaccine efficacy, but frequent monitoring of protection and surveillance of the evolution of the B. pertussis population remains of particular importance.

Diphtheria-tetanus-pertussis (DTP) combination vaccines based on inactivated whole-cell Bordetella pertussis (DTPw) or purified acellular pertussis components (DTPa) facilitate vaccine administration and will allow further co-administration such as with pneumococcal conjugates. Safety and immunogenicity studies are needed to demonstrate non-inferiority between combinations and the separate vaccines. The immunological non-inferiority is based on threshold antibody levels that represent correlates of protection. However, in case of pertussis, correlates of protection have not been defined or accepted. We describe the clinical evaluation of DTPa- and DTPw-based combinations and demonstrate their immunological non-inferiority as compared to their separately administered licensed counterparts. With respect to antibody responses against pertussis, a number of evaluations (vaccine response rates and geometric mean concentrations (GMCs) for anti-PT, anti-FHA, anti-PRN or anti-BPT; reverse cumulative distribution curves) are described. We also demonstrate that the B. pertussis mouse lung clearance model is able to predict clinical efficacy of licensed DTPa and DTPw vaccines and represents a useful tool to evaluate new combination vaccines.

An immunogenic composition comprising FHA and pertussis toxin and further comprising a polypeptide comprising a) an amino acid sequence having an identity of at least 85% with the amino acid sequence of SEQ ID NO: 34, along the full length of SEQ ID NO: 34, or b) an immunogenic fragment having at least 15 contiguous amino acids of SEQ ID NO: 34, and a pharmaceutically acceptable excipient.

Background: Development is ongoing to increase the serotype coverage of pneumococcal conjugate vaccines. We report here the immunogenicity and safety of a new 11-valent pneumococcal conjugate vaccine (Pn-PD) in infants. Methods: In a randomized, single blind study, 154 Finnish infants received 1 of 3 regimens: 4 doses of Pn-PD at 2, 4, 6 and 12–15 months; 3 doses of the Pn-PD at 2, 4 and 6 months and 1 dose of 23-valent polysaccharide vaccine (PncPS) at 12–15 months; or 3 doses of the hepatitis B vaccine at 2, 4 and 6 months and Pn-PD at 12–15 months. Serum IgG antibodies to vaccine serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F were measured with an enzyme immunoassay at the ages of 2, 7 and 12–15 months and at 4 or 28 days after the last vaccination. Local and systemic reactions were recorded by parents during 8 days after each dose. Serious adverse reactions were recorded during the entire study period. Results: There was a significant increase in the IgG concentrations to vaccine serotypes after 3 doses of Pn-PD. Antibody concentrations after the primary series varied between 1.26 and 4.92 &mgr;g/ml depending on the serotype and study group. PncPS vaccine induced a better booster response than the Pn-PD, measured at 28 days after the fourth dose. IgG concentrations after the Pn-PD booster ranged between 1.60 and 9.63 &mgr;g/ml and after the PncPS booster between 4.24 and 40.54 &mgr;g/ml, depending on the serotype. The antibody concentrations after the first dose of Pn-PD administered at 12–15 months increased significantly but were lower than after the fourth dose at the same age. No significant antibody increase was measured 4 days after the vaccinations at 12–15 months. The safety profile of the vaccine was acceptable. Conclusions: The Pn-PD we tested was immunogenic and safe in infants.

The widespread use of whole-cell pertussis vaccines in the second half of the 20th century have reduced the incidence of the disease significantly. However, in some countries, concerns about the reactogenicity and potential neurological damage associated with whole-cell vaccines led to a decrease in vaccine acceptance and an increase in morbidity and mortality of pertussis in several countries. This prompted the development of less reactogenic acellular pertussis vaccines combined with diphtheria and tetanus toxoids, initially in Japan and later in other countries. In Europe, the improved diphtheria, tetanus and acellular pertussis (DTPa) vaccine was first introduced in March 1994. The pertussis component of this DTPa vaccine, developed by Glaxo SmithKline, consists of pertussis toxoid, filamentous haemagglutinin and pertactin. The vaccine is well tolerated, with a lower incidence of adverse reactions than after administration of whole-cell vaccines.The long-lasting efficacy and effectiveness of DTPa vaccines have been extensively documented and these are now the cornerstone of a large range of combined vaccines including DTPa-hepatitis B (HBV), DTPa-inactivated polio (IPV) and DTPa-HBV-IPV. A lyophilised Haemophilus influenzae type b (Hib) vaccine can be reconstituted with all of these liquid combinations. The introduction of well-tolerated and efficacious DTPa vaccines and their more polyvalent combinations has improved the acceptance and simplified the implementation of childhood immunisation. This paper is a review of the technical and scientific difficulties encountered and the lessons learned over the 10-year period that it took to develop and introduce six multivalent vaccines using the Glaxo SmithKline DTPa as a building block. (C) 2003 Elsevier Science Ltd. All rights reserved.

Adsorption of the pertussis antigens, pertussis toxoid (PT), filamentous hemagglutinin (FHA) and pertactin (PRN) onto aluminium phosphate rather than aluminium hydroxide leads to a lower humoral response and poorer protection against intranasal pertussis challenge in mice. These effects could be reversed by inclusion of fimbriae (FIM) 2 and 3 in the formulation. These data emphasis the importance of correct formulation for such vaccines.

Neisseria meningitidis, an exclusive human pathogen, is a major cause of mortality due to meningococcal meningitis and sepsis in many developing countries. Three meningococcal serogroup B proteins, i.e. T-cell stimulating protein A (TspA), autotransporter A (AutA), and IgA-specific serine endopeptidase (IGA1) elicits CD4+ T-cell response and may enhance the effectiveness of meningococcal vaccines by acting as protective immunogens. A very limited data on T-helper cell epitopes in MenB proteins is available. Hence, in silico prediction of peptide sequences which may act as helper T lymphocyte epitopes in MenB proteins was carried out by NetMHCIIpan web server. HLA distribution analysis was done by using the population coverage tool of Immune Epitope Database to determine the fraction of individuals in various populations expected to respond to a given set of predicted T-cell epitopes based on HLA genotype frequencies. Six epitopic core sequences, two from each MenB proteins, i.e. AutA, TspA and IgA1 protease were predicted to associate with a large number of HLA-DR alleles. These six peptides may act as T-cell epitope in more than 95% of populations in 8 out of 12 populations considered. The T-cell stimulation potential of these predicted peptides containing the core epitopic sequences is to be validated by using laboratory experiments for their efficient use as peptide vaccine candidates against N. meningitidis serogroup B.

Combination vaccines are essential to enable administration of all the required antigens in routine infant immunisation schedules at any single visit. Some combinations of diphtheria–tetanus–acellular pertussis (DTPa) with Haemophilus influenzae type b (Hib) conjugate vaccines have been shown to result in lower Hib titres than when Hib is administered separately. While confirming that a primary series with a DTPa–HBV–IPV/Hib combination gives lower antibody levels than separate Hib conjugates, we show that the nature (isotype and IgG subclasses) and function (avidity and opsonic activity) of the antibodies are the same, and immunologic memory is induced. It is likely therefore that the DTPa–HBV–IPV/Hib combination will be efficacious against Hib disease.

The immunogenicity of two meningococcal outer membrane vesicle (OMV) vaccines, namely the Norwegian wild-type OMV vaccine and the Dutch hexavalent PorA OMV vaccine, were examined in infant cynomolgus monkeys. For the first time, a wild-type- and a recombinant OMV vaccine were compared. Furthermore, the induction of memory and the persistence of circulating antibodies were measured. The Norwegian vaccine contained all four classes of major outer membrane proteins (OMP) and wild-type L3/L8 lipopolysaccharide (LPS). The Dutch vaccine consisted for 90% of class 1 OMPs, had low expression of class 4 and 5 OMP, and GalE LPS. Three infant monkeys were immunised with a human dose at the age of 1.5, 2.5 and 4.5 months. Two monkeys of each group received a fourth dose at the age of 11 months. In ELISA, both OMV vaccines were immunogenic and induced booster responses, particularly after the fourth immunisation. The Norwegian vaccine mostly induced sero-subtype P1.7,16 specific serum bactericidal antibodies (SBA), although some other SBA were induced as well. The antibody responses against P1.7,16, induced by the Norwegian vaccine, were generally higher than for the Dutch vaccine. However, the Dutch vaccine induced PorA specific SBA against all six sero-subtypes included in the vaccine showing differences in the magnitude of SBA responses to the various PorAs.

A genetically modified blister preparation from a Gram negative bacterial strain of Neisseria, Moraxella catharralis or Haemophilus influenzae, characterized in that said preparation can be obtained using the following procedure: d) a procedure for modifying the lipid part A of bacterial LPS within the ampoule preparation, which comprises the steps of identifying an msbB gene involved in making the lipid part of LPStoxic, genetically modifying a bacterial strain to reduce or inactivating the expression of said gene, and manufacturing blisters from said strain

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.