Safety of pentavalent DTaP-IPV/Hib combination vaccine in post-marketing surveillance in Guangzhou, China, from 2011 to 2017.

BACKGROUND: The DTaP-IPV/Hib combination vaccine can replace the acellular tetanus vaccine, polio vaccine, and the Haemophilus influenzae type B vaccine. Data on the safety of DTaP-IPV/Hib vaccines are required. We aimed to evaluate the safety of the vaccination program. METHODS: Using the National Adverse Events Following Immunization (AEFI) surveillance system (CNAEFIS) in Guangzhou, China, a retrospective study was performed from May 11, 2011, to December 31, 2017. There were 376 cases of adverse events after vaccination with the DTaP IPV/Hib vaccine. The primary analysis indicators were the number of vaccines used, the number of AEFI reports received, and the reporting rate (per 100,000). RESULTS: From May 1, 2011, to December 31, 2017, 516,000 doses of vaccine were inoculated, and 376 cases of adverse reactions were reported; the reporting rate was 72.8 per 100,000 vaccines. There were eight cases of serious AEFIs (1.5 per 100,000), with four cases of thrombocytopenic purpura (0.8 per 100,000); three cases of cyanosis of the lips, stiffness, and flexion of limbs, and convulsions (0.6 per 100,000); and one case of a high fever (0.2 per 100,000). The highest incidence of AEFIs occurred after the fourth dose (n = 207, 55.0%, 40.1 per 100,000), followed by the first dose (n = 81, 21.5%, 15.7 per 100,000), second dose (n = 48, 12.8%, 9.3 per 100,000) and third dose (n = 40, 10.6%, 7.7 per 100,000). The AEFI incidence was higher after injection of the vaccine into the deltoid muscle of the upper arm (n = 276, 73.4%, 53.5 per 100,000) than after injection of the vaccine into the thigh (n = 100, 26.6%, 19.4 per 100,000). There was a significant difference between AEFIs after injection into the deltoid of the upper arm deltoid and the thigh (x2 = 164.8, P < 0.05). CONCLUSIONS: Most of the reported AEFIs after DTaP-IPV/Hib vaccination are not serious. There were four cases of TP in this study; vaccination may be a rare cause of thrombocytopenic purpura.

DTaP-IPV-HepB-Hib Vaccine (Hexyon®): An Updated Review of its Use in Primary and Booster Vaccination.

Hexyon® is a fully-liquid, ready-to-use, hexavalent vaccine approved in the EU since 2013 for primary and booster vaccination in infants and toddlers from age 6 weeks against diphtheria, tetanus, pertussis, hepatitis B (HB), poliomyelitis, and invasive diseases caused by Haemophilus influenzae type b (Hib). While the source of HB antigen in Hexyon® is different from other vaccines, the rest of its valences have been extensively used in other approved vaccines. Hexyon® is highly immunogenic for all its component toxoids/antigens when used as primary and booster vaccine in infants and toddlers, irrespective of vaccination schedule. It provides durable protection against hepatitis B. Hexyon® can be used for a mixed primary series of hexavalent-pentavalent-hexavalent vaccines or as a booster in infants primed with Infanrix hexa™ or pentavalent (whole-cell or acellular pertussis) vaccines. Coadministration of Hexyon® with other common childhood vaccines did not affect immune response to any vaccines. Hexyon® has a good reactogenicity/safety profile. The immunogenicity and safety profile of Hexyon® was similar to that of several approved vaccines, including Infanrix hexa™. However, Hexyon® offers the convenience of full-liquid, ready-to-use formulation, which may minimize vaccination errors and preparation time. Thus, Hexyon® is a convenient, useful option for vaccination against childhood diseases caused by six major pathogens.

Selection of Avibacterium paragallinarum Page serovar B strains for an infectious coryza vaccine.

Infectious coryza is an important respiratory disease of chickens around the world and is caused by Avibacterium paragallinarum. Among the three Page serovars currently recognized for this bacterium, serovar B is a major circulating serovar in China nowadays. The cross-protection ability of the Page serovar B reference strain (0222) and five local isolates was evaluated by a vaccination-challenge trial in SPF chickens. The clinical signs seen in control birds challenged by strain 0222 and isolate HB 01 were significantly different, with isolate HB 01 giving more severe clinical signs. In terms of cross-protection, the protection in the groups vaccinated with isolate HB 01 and BJ 02 was significantly higher than that in the groups vaccinated with 0222 and the other three isolates. In addition, an experimental oil adjuvant trivalent vaccine, containing field isolate HB 01 antigen, was compared for immune efficacy with two commercial trivalent infectious coryza vaccines containing internationally recognized serovar B strains. The experimental oil adjuvant trivalent vaccine elicited best protection (80%) among the three trivalent vaccines. In conclusion, the oil adjuvant vaccine, containing field isolate HB 01 may be a better choice in control of current serovar B Av. paragallinarum outbreaks in China under current circumstances.

Protective Efficacy of an Inactive Vaccine Based on the LY02 Isolate against Acute Haemophilus parasuis Infection in Piglets.

Haemophilus parasuis can cause Glässer's disease characterized by fibrinous polyserositis, polyarthritis, and meningitis. The current prevention of Glässer's disease is mainly based on the inactive vaccines; however, the protective efficacy usually fails in heterogeneous or homologous challenges. Here, the predominant lineage of H. parasuis (LY02 strain) in Fujian province, China, characterized as serovar 5, was used to evaluate the protective immunity against acute H. parasuis infection in piglets after inactivation. Following challenging with H. parasuis, only mild lesions in the pigs immunized with the killed vaccine were observed, whereas the typical symptoms of Glässer's disease presented in the nonimmunized piglets. A strong IgG immune response was induced by the inactive vaccine. CD4(+) and CD8(+) T lymphocyte levels were increased, indicating the potent cellular immune responses were elicited. The significantly high levels of IL-2, IL-4, TGF-ß, and IFN-γ in sera from pigs immunized with this killed vaccine suggested that the mixed Th1 and Th2 immune responses were induced, associated with the high protection against H. parasuis infection compared to the nonimmunized animals. This study indicated that the inactivated LY02 strain of H. parasuis could serve as a potential vaccine candidate to prevent the prevalence of H. parasuis in Fujian province, China.

MenHibrix: a new combination meningococcal vaccine for infants and toddlers.

OBJECTIVE: To review the immunogenicity and safety of the Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y tetanus toxoid conjugate vaccine (Hib-MenCY-TT) for infants and toddlers. DATA SOURCES: Studies conducted in humans and limited to publication in English were identified through a MEDLINE (January 2000 to September 2013) search using the terms Hib-MenCY-TT, MenHibrix, and Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y tetanus toxoid conjugate vaccine. Clinical trial registries, Web sites, and reference citations from publications identified were reviewed for additional sources. STUDY SELECTION AND DATA EXTRACTION: Randomized controlled trials were included to evaluate the safety and immunogenicity of Hib-MenCY-TT. Epidemiological data and recommendations from the Advisory Committee on Immunization Practices (ACIP) were also reviewed. DATA SYNTHESIS: Hib-MenCY-TT is available for primary vaccination of infants as a 4-dose series at 2, 4, 6, and 12 to 15 months of age. Hib-MenCY-TT has comparable immunogenicity to licensed Hib vaccines and produces high levels of N meningitidis antibodies against serogroups C and Y. The most common adverse events were pain and redness at the injection site, drowsiness, and irritability. CONCLUSIONS: Hib-MenCY-TT has been demonstrated to be a safe and immunogenic vaccination for prevention of disease caused by N meningitidis serogroups C and Y and H influenzae type b in healthy infants and toddlers. Currently, the ACIP recommends the use of Hib-MenCY-TT specifically in high-risk infants aged 6 weeks to 18 months. Hib-MenCY-TT provides the first therapeutic option for vaccination of infants as young as 6 weeks of age who are at increased risk for meningococcal disease.

Expression of hBD-2 induced by 23-valent pneumococcal polysaccharide vaccine, Haemophilus influenzae type b vaccine and split influenza virus vaccine.

Human ß-defensin-2 (hBD-2) is an antimicrobial peptide with high activity and broad spectrum activity. hBD-2 expression may be highly elevated by microorganisms and inflammation. We reported that the majority of common vaccines used, including 23-valent pneumococcal polysaccharide vaccine, Haemophilus influenzae type b vaccine and split influenza virus vaccine, could induce the expression of hBD-2 in epithelial cells. Among them, the 23-valent pneumococcal polysaccharide vaccine was effective at a lower concentration (0.5 µg/ml), while Haemophilus influenzae type b vaccine and split influenza virus vaccine were effective at the concentration of 1 µg/ml. However, bacteriostatic experiments revealed that the split influenza virus vaccine was capable of inducing the highest antimicrobial activity. The medium of the 23-valent pneumococcal polysaccharide vaccine treatment group had a higher antimicrobial activity than the medium of the Haemophilus influenzae type b vaccine treatment group. The transcriptional regulator of hBD-2, that is, the NF-κB subunit, had a high level of activity, while the normal epithelial cells showed barely detectable activity, indicating that these vaccines have potential for clinical application.

A single nasal dose of CCL20 chemokine induces dendritic cell recruitment and enhances nontypable Haemophilus influenzae-specific immune responses in the nasal mucosa.

CONCLUSION: The results of the present study indicate the potential of CCL20 as an effective mucosal adjuvant and suggest that nasal vaccination with P6 in combination with nasal CCL20 might be an effective regimen for the induction of nontypable Haemophilus influenzae (NTHi)-specific protective immunity. OBJECTIVES: Nasal vaccination is an effective therapeutic regimen for preventing upper respiratory infections. In the development of nasal vaccine, an appropriate adjuvant is required. In the present study we examined the efficacy of CCL20 as a mucosal adjuvant. METHODS: CCL20 was administered intranasally to mice, which were then immunized intranasally with P6 protein of NTHi, and P6-specific immune responses were examined. In addition, NTHi challenges were performed and the level of NTHi was quantified in nasal washes. RESULTS: Nasal application of CCL20 induced an increase in the number of dendritic cells in nasal-associated lymphoid tissue. P6-specific nasal wash immunoglobulin (Ig)A and serum IgG titers were elevated significantly after nasal immunization. Enhanced NTHi clearance from the nasopharynx was also observed.

Spotlight on DTPa-HBV-IPV/Hib Vaccine (Infanrix hexa).

Infanrix hexa, administered intramuscularly, is a diphtheria, tetanus, acellular pertussis, hepatitis B (HBV), inactivated poliomyelitis and Haemophilus influenzae type b (Hib) conjugate vaccine, indicated for primary and booster vaccination of infants. Infanrix hexa should be administered as a two- or three-dose primary vaccination course in infants aged < or =6 months, followed by booster vaccination between 11 and 18 months of age, with an interval of at least 6 months between the last dose of primary vaccination and the booster dose. This spotlight reviews the immunogenicity and protective effectiveness, as well as the reactogenicity and safety of Infanrix hexa. Infanrix hexa as primary and booster vaccination was safe and highly immunogenic for all its component toxoids/antigens in infants aged <2 years, regardless of vaccination schedules. Its immunogenicity and safety profiles were generally similar to those of currently available vaccines, the diphtheria, tetanus and acellular pertussis-based pentavalent vaccines plus monovalent HBV or Hib vaccines. In large clinical studies, Infanrix hexa elicited a strong immune response against vaccine toxoids/antigens, as indicated by high seroprotection/seropositivity/vaccine response rates and geometric mean titers. Moreover, antibodies against vaccine toxoids/antigens persisted for up to a mean of approximately 6 years after booster vaccination, and the vaccine induced long-term immune memory against hepatitis B surface antigen and Hib antigen. A strong immune response against Infanrix hexa toxoids/antigens after primary vaccination was also induced in infants who had received a dose of HBV vaccine at birth and in pre-term infants, although the response in the latter group was somewhat lower than that in full-term infants. In addition, when coadministered with other childhood vaccines, the immunogenicity of Infanrix hexa or that of the concomitantly administered vaccine was generally not altered. Hexavalent vaccines, including Infanrix hexa, were protective against invasive Hib disease; Infanrix hexa is also expected to be protective against pertussis. Most solicited local and general symptoms with Infanrix hexa were mild to moderate in intensity and the vaccine was associated with few unsolicited adverse events. Available clinical data from more than 10 years' experience with the vaccine suggest that Infanrix hexa as primary and booster vaccination is a safe and useful option for providing protection against the common childhood diseases of diphtheria, tetanus, poliomyelitis, pertussis, hepatitis B and invasive Hib disease.

The immunological response of Thai infants to haemophilus influenzae type B polysaccharide-tetanus conjugate vaccine co-administered in the same syringe with locally produced diphtheria-tetanus-pertussis vaccine.

OBJECTIVE: Comparing the immunogenicity and reactogenicity of three vaccine combinations. These were GlaxoSmithKline Biologicals' (GSK) Haemophilus influenzae type b vaccine (Hib-TT, Hiberix) administered with the local Government Pharmaceutical Organization's (GPO) diphtheria-tetanus-pertussis whole cell (DTPw) vaccine, Hib-TT mixed with GPO's DTPw vaccine, or Hib-IT mixed with GSKs' DTPw vaccine (Tritanrix). MATERIAL AND METHOD: An open, randomized, controlled, single center study of three hundred and sixty infants. They were randomized into three groups to receive either Hib-TT Hiberix mix with GPOs' DTPw vaccine (group 1), Hib-TT mixed with GPO's DTPw vaccine (group 2), or Hib-TT mixed with GSKs' DTPw vaccine (Tritanrix; group 3) at two, four and six months of age. RESULT: One month after the third dose, all subjects had antibodies level against Hib polyribosylribitol phosphate (PRP) > or = 0.15 microg/ml. All 11 subjects except two (in group 2) had anti-PRP levels > or = 1.0 microg/ml. The geometric mean concentrations were similar in all three groups. Over 96% of the subjects in all three groups demonstrated an immunological response to diphtheria, tetanus, and pertussis antigens. There was no diference among the three groups in terms of severe local reaction and fever. CONCLUSION: The present study showed that the combined vaccines produced an effective antibody response with no increase in reactogenicity compared to separately administrated vaccines.

Investigation of the potential of a 48 kDa protein as a vaccine candidate for infection against nontypable Haemophilus influenzae.

This study determined the conservation and protective efficacy of a 48 kDa nontypable Haemophilus influenzae (NTHi) protein (P48). This protein was highly conserved across the strains of NTHi examined and mucosal immunization with recombinant P48 (rP48) significantly reduced the numbers of viable NTHi recovered from the lung following challenge. rP48 induced predominantly an IgG2a antibody response that correlated with the reduction in the number of viable NTHi in the lung. These antibodies were not bactericidal against NTHi. The results suggest that P48 warrants further investigation as a vaccine component for NTHi disease.

Vaccine development for capsulate bacteria causing pneumonia.

Pneumonia strikes the extremes of the age spectrum, causing maximal death and disability in children and the elderly. Despite its worldwide impact, there is a paucity of epidemiologic data regarding its incidence and the causative organisms. The two leading causes of bacterial pneumonia in childhood are Streptococcus pneumoniae (SP) and Haemophilus influenzae type b (Hib). SP is the major cause of pneumonia beyond the newborn period. In neonates, Group B Streptococcus (GBS) remains a major cause of sepsis and pneumonia despite recent reductions due to targeted perinatal antibiotic prophylaxis. Hib vaccine can prevent pneumonia in developing countries. SP conjugate vaccine prevents X-ray confirmed pneumonia in low incident populations, but protection appears more marginal in high incident populations. Non-vaccine SP serotypes have demonstrated increased carriage and mucosal disease, but not invasive disease following vaccination. GBS vaccines are in the early stages of clinical development as prenatal or antenatal vaccines.

Intranasal immunization with recombinant outer membrane protein P6 induces specific immune responses against nontypeable Haemophilus influenzae.

OBJECTIVE: Nontypeable Haemophilus influenzae (NTHi) is one of the leading causative pathogens for otitis media. The outer membrane protein P6 of NTHi is highly conserved among the strains and is an attractive candidate for a preventive vaccine. However, for the production of a relatively small amount P6 containing lipopolysaccharides, the development of a recombinant version of this protein is required. This study was designed to investigate the specific mucosal immunity induced by intranasal immunization of recombinant P6 (rP6) with cholera toxin (CT). METHODS: BALB/c mice were immunized with of rP6 (30 microg) and CT (2 microg) intranasally every 2 days for 2 weeks. Anti-rP6 specific IgG, IgA and IgM antibodies and the subclass of anti-rP6 specific IgG antibody were determined by enzyme linked immunosorbent assay (ELISA). Anti-rP6 specific IgA in nasopharyngeal washings were also determined by ELISA. Nasopharyngeal clearance of inoculated NTHi after the intranasal immunization were assessed. All statistical differences between the two groups were assessed by ANOVA parametric test. RESULTS: Intranasal immunization with rP6 and CT evoked rP6-specific mucosal IgA immune response as well as the systemic IgG immune response against rP6 and enhanced nasopharyngeal clearance of inoculated live NTHi. CONCLUSION: These results indicate the good immunogenicities of rP6 to induce specific immune responses against NTHi. Intranasal immunization with rP6 will be an effective approach to protect infections of NTHi.

Reduced effectiveness of Haemophilus influenzae type b conjugate vaccine in children with a high prevalence of human immunodeficiency virus type 1 infection.

BACKGROUND: Haemophilus influenzae type b (Hib) conjugate vaccines have successfully reduced the burden of invasive Hib disease in developed countries; however, their effectiveness in countries with a high incidence of pediatric HIV-1 is unknown. METHODS: The effectiveness of Hib conjugate vaccine was prospectively evaluated in South African children. The burden of invasive Hib disease in children < 1 year old was compared in 2 cohorts. The first cohort included 22,000 African children born in 1997 [969 (4.45%) of whom were estimated to be HIV-1-infected] who were not vaccinated with Hib conjugate vaccine. This group was compared with 19,267 children [1162 (6.03%) of whom were estimated to be HIV-1 infected] vaccinated at 6, 10 and 14 weeks of age with an Hib conjugate vaccine [TETRAMUNE (polyribosylribitol phosphate-CRM(197)-diphtheria-tetanus toxoids-whole cell pertussis)] between March, 1998, and June, 1999. RESULTS: The estimated burden of invasive Hib disease in nonimmunized HIV-1-infected children < 1 year of age was 5.9-fold [95% confidence interval (95% CI), 2.7 to 12.6] higher than in HIV-1-uninfected children. The overall estimated effectiveness of Hib conjugate vaccine in fully vaccinated children <1 year of age was 83.2% (95% CI 60.3 to 92.9). Vaccine effectiveness was significantly reduced in HIV-1-infected [43.9% (95% CI -76.1 to 82.1)] compared with uninfected children [96.5% (95% CI 74.4 to 99.5); P < 10(-5)]. Among three of the fully vaccinated HIV-1-infected children who developed invasive Hib disease, the anti-Hib polyribosylribitol phosphate serum antibody concentrations were 0.23, 0.25 and 0.68 microg/ml. CONCLUSION: Although the Hib conjugate vaccine was less effective among HIV-1-infected than among uninfected children, it was 83% effective in preventing overall invasive Hib disease and therefore should be considered for inclusion in the routine vaccination schedule by other African countries.

Evolutionary and immunological implications of contemporary HIV-1 variation.

Evolutionary modelling studies indicate less than a century has passed since the most recent common ancestor of the HIV-1 pandemic strains and, in that time frame, an extraordinarily diverse viral population has developed. HIV-1 employs a multitude of schemes to generate variants: accumulation of base substitutions, insertions and deletions, addition and loss of glycosylation sites in the envelope protein, and recombination. A comparison between HIV and influenza virus illustrates the extraordinary scale of HIV variation, and underscores the importance of exploring innovative HIV vaccine strategies. Deeper understanding of the implications of variation for both antibody and T-cell responses may help in the effort to rationally design vaccines that stimulate broad cross-reactivity. The impact of HIV-1 variation on host immune response is reviewed in this context.

Economic evaluation of Haemophilus influenzae type b vaccination in Slovenia.

The objective of the present study was to assess the economical impact of invasive Haemophilus influenzae type b infections in Slovenia, where the annual incidence of these infections is 16.4/100000 in children less than 5 years of age, and to compare it with the costs of a vaccination programme. The lifetime costs and benefits were estimated for the annual birth cohort of 18200 children. In the base-case model, the calculated benefit-to-cost ratios were 0.15, 0.98 and 1.38 taking into account 95% of savings in acute care costs, medical costs, and medical and non-medical costs, respectively. From the point of view of the Institute of Health Insurance of Slovenia, who pays all healthcare and vaccination costs, the vaccination programme per annual birth cohort of 18200 children would require an extra 7023 EUR or 0.40 EUR per cohort-child. The savings to society would represent 118410 EUR, indicating the rationale for inclusion of H. influenzae type b vaccination in the routine childhood immunisation programme in Slovenia.

Conjugates and reverse vaccinology to eliminate bacterial meningitis.

Bacterial meningitis is caused mainly by Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis. Haemophilus influenzae type b vaccines have been extremely successful in eradicating the disease from those countries where the vaccine has been introduced. The recent licensure of the conjugated pneumococcal vaccine suggests that this pathogen also will be soon controlled. Consequently, if we succeed in developing effective vaccines against meningococcus, this will enable us to eliminate bacterial meningitis. The global elimination of bacterial meningitis is a goal which, if appropriate resources are applied, can be reached within the first fifteen years of the 21st century.

Peptide and recombinant antigens for protection against bacterial middle ear infection.

Passive immunization of chinchillas with serum specific for either LB1 or for LPD-LB1 (f)(2,1,3) prior to challenge with heterologous NTHI isolates (relative to diversity in region three of P5-fimbrin), significantly inhibited the signs and incidence of otitis media (P < or = 0.01) induced by any of the challenge isolates. The ability of these antisera to induce total eradication of NTHI from the nasopharynx was not however equivalent among challenged cohorts. The data thus suggested that while early, complete eradication of NTHI from the nasopharynx was highly protective, reduction of the bacterial load to below a critical threshold level appeared to be similarly effective. Both immunogens thus remain strong vaccine candidates.

Meningitis and septicaemia in a child caused by non-typable Haemophilus influenzae biotype III.

Since vaccination against Haemophilus influenzae type b (Hib) became widespread, other strains of H. influenzae have become more common than Hib as causes of disease in vaccinated children. A four-month-old, appropriately vaccinated infant presented with meningitis and septicaemia caused by H. influenzae biotype III. To our knowledge, this is the first reported case of meningitis caused by this biotype, which is not detectable by Hib antigen tests.

New methods for the characterisation of biopharmaceuticals: conjugate vaccines against Haemophilus influenzae type b.

Modern physicochemical methods allow biological pharmaceuticals, particularly those arising from recombinant DNA technology, to be characterised with a degree of precision not previously possible. These techniques, which tell us what a material is (rather than what it does) provide an approach complementary to traditional bioassays for the control of biological pharmaceuticals. As we come to understand the mechanisms by which structural variation modulates the various biological activities of a product, structure-based assays will be able to replace biological identity and potency assays, although replacement of safety tests to find trace impurities (such as endotoxin) may be more difficult.