Long-term follow-up of Japanese encephalitis chimeric virus vaccine: Immune responses in children

BackgroundA single dose of live attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) was shown to be immunogenic and well tolerated when given either as a booster to formalin-inactivated Japanese encephalitis (JE)-vaccine (mouse brain-derived vaccine [MBDV])-primed 2–5-year-olds, or as a primary vaccination to JE-vaccine-naïve 12–24-month-old toddlers in Thailand. A 5-year follow-up assessment of immune response persistence over time was conducted.MethodsFour additional visits (at 2, 3, 4, and 5 years) for immunologic assessments were added to the original 12-month open-label crossover study, in which 100 healthy children aged 2–5 years with a history of two-dose primary vaccination with MBDV (according to the Thai Expanded Program for Immunization schedule), and 200 healthy JE-vaccine-naïve 12–24-month-old toddlers, were randomized 1:1 to receive JE-CV, containing ⩾4 log₁₀ plaque forming units, 1 month before or after hepatitis A control vaccine.ResultsIn MBDV-primed 2–5-year-olds (n = 78), the immune response to the JE-CV vaccine persisted up to at least 5 years after vaccination with a single dose of JE-CV, with all (n = 78) children seroprotected at the year 5 visit (geometric mean titers [GMT]: 252 1/dil). There was no decrease of seroprotection rate over time (100% at 6 months post-vaccination and 96.8% (90.3–98.9) at 5 years post-vaccination). In JE-vaccine-naïve toddlers, a protective immune response persisted up to at least 5 years in 58.8% (50.9–66.4) after a single-dose administration of JE-CV (GMT 26.7 1/dil; sensitivity analysis).ConclusionsA single-dose of JE-CV as a booster following MBDV administration provided long-lasting immunity. In JE-vaccine-naïve toddlers, despite relatively high seroprotection rates persisting over time, a subsequent booster dose is recommended following a JE-CV primary vaccination for long-term protection.This study was registered on www.clinicaltrials.gov (NCT00621764).     

Immunogenicity of live attenuated Japanese encephalitis SA 14-14-2 vaccine among Sri Lankan children with previous receipt of inactivated JE vaccine

BackgroundThe performance of live attenuated Japanese Encephalitis SA 14-14-2 vaccine (CD-JEV) among children previously given inactivated mouse brain-derived JE vaccine (IMBV) is unknown. We evaluated the safety and immunogenicity of CD-JEV administered to 2- and 5-year-old children in Sri Lanka.MethodsIn this open-label, single arm trial in the Colombo District of Sri Lanka, generally healthy children 2 and 5 years of age who had previously received two and three doses of IMBV, respectively, were administered one dose of CD-JEV subcutaneously. Participants were monitored for adverse events for one year post-vaccination. Serum neutralizing antibody responses were evaluated pre and 28 and 365 days post-vaccination using JE plaque reduction neutralization test and characterized as the proportion of participants seroconverting. Seroconversion was defined as either reaching a titer considered seroprotective (⩾1:10) among participants with a baseline titer <1:10 or achieving at least a 4-fold rise in titer among participants with a baseline titer ⩾1:10.ResultsOf 305 children given CD-JEV, 294 were included in the primary analysis of immunogenicity. Prior to vaccination, 144/147 (98.0%) 2-year-olds and 146/147 (99.3%) 5-year-olds had seroprotective levels. 28 days post-vaccination, 79/147 [53.7% (95% CI, 45.3–62.0)] 2-year olds and of 60/147 [40.8% (95% CI, 32.8–49.2)] 5-year olds achieved seroconversion. Among 2-year-olds, geometric mean titers (GMTs) rose from 697 to 3175 28 days post-vaccination. Among 5-year-olds, GMTs rose from 926 to 2776. Most adverse reactions were mild, and no serious adverse events were related to study vaccination.ConclusionAdministration of CD-JEV to these children with pre-existing neutralizing JE antibody titers was safe and resulted in substantial boosting of antibody levels. These results may inform other countries in Asia considering switching from IMBV to now WHO-prequalified CD-JEV vaccine to combat this disease of public health importance.     

Post-licensure,phase IV,safety study of a live attenuated Japanese encephalitis recombinant vaccine in children in Thailand

BackgroundJapanese encephalitis is a mosquito-borne viral disease endemic in most countries in Asia. A recombinant live, attenuated Japanese encephalitis virus vaccine, JE-CV, is licensed in 14 countries, including Thailand, for the prevention of Japanese encephalitis in adults and children.MethodsThis was a prospective, phase IV, open-label, multicentre, safety study of JE-CV conducted from November 2013 to April 2015, to evaluate rare serious adverse events (AEs). JE-CV was administered to 10,000 healthy children aged 9 months to <5 years in Thailand as a primary (Group 1) or booster (Group 2) vaccination. Serious AEs (SAEs), including AEs of special interest, up to 60 days after administration were evaluated. Immediate Grade 3 systemic AEs up to 30 min after JE-CV administration were also described.ResultsThe median age of participants was 1.1 years in Group 1 and 3.8 years in Group 2. SAEs were reported in 204 (3.0%) participants in Group 1 and 59 (1.9%) participants in Group 2. Among a total of 294 SAEs in 263 participants, only three events occurring in two participants were considered related to vaccination. All three cases were moderate urticaria, none of which met the definition of AEs of special interest for hypersensitivity. AEs of special interest were reported in 28 (0.4%) participants in Group 1 and 4 (0.1%) participants in Group 2; none were considered related to vaccination. Febrile convulsion was the most frequently reported AE of special interest: 25 (0.4%) participants in Group 1; and 2 (<0.1%) in Group 2. There were no cases of Japanese encephalitis reported. No Grade 3 immediate systemic AEs were reported after any JE-CV vaccination.ConclusionsOur study did not identify any new safety concerns with JE-CV and confirms its good safety profile.This study was registered on www.clinicaltrials.gov (NCT01981967; Universal Trial Number: U1111-1127-7052).     

Rift Valley fever MP-12 vaccine Phase 2 clinical trial: Safety,immunogenicity, and genetic characterization of virus isolates

An outbreak or deliberate release of Rift Valley fever (RVF) virus could have serious public health and socioeconomic consequences. A safe RVF vaccine capable of eliciting long-lasting immunity after a single injection is urgently needed. The live attenuated RVF MP-12 vaccine candidate has shown promise in Phase 1 clinical trials; no evidence of reversion to virulence has been identified in numerous animal studies. The objective of this Phase 2 clinical trial was to (a) further examine the safety and immunogenicity of RVF MP-12 in RVF virus–naïve humans and (b) characterize isolates of RVF MP-12 virus recovered from the blood of vaccinated subjects to evaluate the genetic stability of MP-12 attenuation. We found that RVF MP-12 was well tolerated, causing mostly mild reactions that resolved without sequelae. Of 19 subjects, 18 (95%) and 19 (100%) achieved, respectively, 80% and 50% plaque reduction neutralization titers (PRNT₈₀ and PRNT₅₀) ≥ 1:20 by postvaccination day 28. All 18 PRNT₈₀ responders maintained PRNT₈₀ and PRNT₅₀ ≥ 1:40 until at least postvaccination month 12. Viremia was undetectable in the plasma of any subject by direct plaque assay techniques. However, 5 of 19 vaccinees were positive for MP-12 isolates in plasma by blind passage of plasma on Vero cells. Vaccine virus was also recovered from buffy coat material from one of those vaccinees and from one additional vaccinee. Through RNA sequencing of MP-12 isolates, we found no reversions of amino acids to those of the parent virulent virus (strain ZH548). Five years after a single dose of RVF MP-12 vaccine, 8 of 9 vaccinees (89%) maintained a PRNT₈₀ ≥ 1:20. These findings support the continued development of RVF MP-12 as a countermeasure against RVF virus in humans.     

Persistence of antibodies six years after booster vaccination with inactivated vaccine against Japanese encephalitis

BackgroundJapanese Encephalitis (JE) virus occurs in wide regions of Asia with over 3 billion people living in areas at risk for JE. An estimated 68,000 clinical cases of JE occur every year, and vaccination is the most effective prophylactic measure. One internationally licensed vaccine containing the inactivated JE virus strain SA₁₄-14-2 is Ixiaro^® (Valneva, Austria). According to recommendations, basic immunization consists of vaccinations on day 0, day 28, and a booster dose 12–24 months later. Protection in terms of neutralizing antibody titers has been assessed up to 12 months after the third dose of the vaccine. The current investigation was designed to evaluate antibody decline over time and to predict long-term duration of seroprotection after a booster dose.MethodIn a preceding trial, volunteers received basic immunization (day 0, day 28) and one booster dose against JE 15 months later. A follow up blood draw 6 years following their booster dose was carried out in 67 subjects. For antibody testing, a 50% plaque reduction neutralization test (PRNT₅₀-test) was used. PRNT₅₀ values of 10 and above are surrogate levels of protection according to WHO standards.ResultSeventy-six months following the booster dose, 96% of the tested subjects had PRNT₅₀ titers of 10 or higher. Geometric mean titer (GMT) was 148 (95% CI confidence interval: 107–207). Antibody titers were lower in volunteers 50 years of age and older. Vaccination history against other flaviviruses (yellow fever or tick borne encephalitis) did not significantly influence PRNT₅₀ titers. A two-step log-linear decline model predicted protection against JE of approximately 14 years after the booster dose.ConclusionSix years after a booster dose against JE, long-term protection could be demonstrated. According to our results, further booster doses should be scheduled 10 years following the first booster dose.     

Contrasting female-male mortality ratios after routine vaccinations with pentavalent vaccine versus measles and yellow fever vaccine. A cohort study from urban Guinea-Bissau

BackgroundIn addition to protection against the target diseases, vaccines may have non-specific effects (NSEs). Measles vaccine (MV) has beneficial NSEs, providing protection against non-measles deaths, most so for girls. By contrast, though protecting against diphtheria, tetanus and pertussis, DTP vaccine is associated with increased female mortality relative to male mortality. In 2008, Guinea-Bissau replaced DTP with the DTP-containing pentavalent vaccine (Penta; DTP-H. influenza type B-Hepatitis B) at 6, 10 and 14 weeks and yellow fever vaccine (YF) was to be given with MV. We investigated possible sex-differential mortality rates following Penta and MV+YF vaccination.MethodsBandim Health Project (BHP) registers vaccines given by the three government health centres in the study area and vital status through demographic surveillance. We assessed the association between sex and mortality by vaccination status in Cox proportional hazards models with age as underlying timescale. Follow-up was censored at a subsequent vaccination contact or after 6 months of follow-up.ResultsBetween September 2008 and April 2011, we registered 23,448 vaccination contacts for children aged 42–365 days; 17,313 were for Penta and 3028 for MV (2907 co-administered with YF). During follow-up 112 children died. The female/male mortality rate ratio was 1.73 (1.11–2.70) following Penta and 0.38 (0.12–1.19) after MV (p = 0.02 for same effect). Adjusting for maternal education or weight-for-age at the time of vaccination did not change the estimates.ConclusionPenta appears to have the same negative effects on mortality as those seen for DTP. Assessing post-vaccination mortality for boys and girls is necessary to improve the vaccination programme.     

Safety and immunogenicity of a mutagenized,live attenuated Rift Valley fever vaccine,MP-12, in a Phase 1 dose escalation and route comparison study in humans

Rift Valley fever (RVF) poses a risk as a potential agent in bioterrorism or agroterrorism. A live attenuated RVF vaccine (RVF MP-12) has been shown to be safe and protective in animals and showed promise in two initial clinical trials. In the present study, healthy adult human volunteers (N = 56) received a single injection of (a) RVF MP-12, administered subcutaneously (SQ) at a concentration of 10^4.7 plaque-forming units (pfu) (SQ Group); (b) RVF MP-12, administered intramuscularly (IM) at 10^3.4 pfu (IM Group 1); (c) RVF MP-12, administered IM at 10^4.4 pfu (IM Group 2); or (d) saline (Placebo Group). The vaccine was well tolerated by volunteers in all dose and route groups. Infrequent and minor adverse events were seen among recipients of both placebo and RVF MP-12. One subject had viremia detectable by direct plaque assay, and six subjects from IM Group 2 had transient low-titer viremia detectable only by nucleic acid amplification. Of the 43 vaccine recipients, 40 (93%) achieved neutralizing antibodies (measured as an 80% plaque reduction neutralization titer [PRNT₈₀]) as well as RVF-specific IgM and IgG. The highest peak geometric mean PRNT₈₀ titers were observed in IM Group 2. Of 34 RVF MP-12 recipients available for testing 1 year following inoculation, 28 (82%) remained seropositive (PRNT₈₀ ≥ 1:20); this included 20 of 23 vaccinees (87%) from IM Group 2. The live attenuated RVF MP-12 vaccine was safe and immunogenic at the doses and routes studied. Given the need for an effective vaccine against RVF virus, further evaluation in humans is warranted.     

Response to the influenza vaccine based on estradiol use in menopausal women

ObjectiveTo assess the impact of 17β-estradiol in modulating the response to the influenza vaccine in postmenopausal women.MethodsA prospective cohort study was conducted with 46 healthy postmenopausal women aged 41–62 years without previous vaccination against the influenza virus. Evaluation of serum antibodies using hemagglutination inhibition and single radial hemolysis was performed at the Virology Laboratory of the Butantan Institute, São Paulo, Brazil, using serum samples collected at two time points: immediately before and one month after vaccination.ResultsIn non-estradiol users (n = 25), the median number of hemagglutination-inhibiting units (Log₂) increased from 5.32 to 6.82 (p = 0.003). In estradiol users (n = 21), the median number of hemagglutination-inhibiting units (Log₂) increased from 5.32 to 5.82 (p = 0.149). The median hemolytic areas produced with the single radial hemolysis assay before and after the vaccine were 11 mm in both groups.ConclusionIn postmenopausal women, estrogen therapy did not have a positive influence on the production of antibodies against the influenza virus after vaccination, at least based on the formulation, time period, and methods used for quantifying these antibodies in the present study.     

Concomitant administration of live attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) and measles,mumps, rubella (MMR) vaccine: Randomized study in toddlers in Taiwan

Background

Japanese encephalitis (JE) is the most important cause of viral encephalitis in Asia.

Methods

In this randomized, open-label, multicenter trial in 550 children aged 12 to 18 months in Taiwan, children received one dose of JE-CV and one dose of MMR vaccine. Vaccines were either administered separately 6 weeks apart (Groups ‘JE-CV’ and ‘MMR’, named after which vaccine was given first), or concomitantly (Group ‘Co-Ad’). JE neutralizing antibody titers were assessed using PRNT₅₀. MMR antibody levels were determined by ELISA.

Results

All groups had low seroprotection/seropositivity rates (<10%) before vaccination for all antigens. Forty two days after vaccination, on either Study Day 42 or 84, seroconversion rates for all antigens were high in all groups, irrespective of the order of vaccinations. Seroconversion for JE ranged from 96.9% in Group Co-Ad on D42 to 100% in Group MMR. Non-inferiority was demonstrated for all analyses as the lower bound of the 95% CI of the difference in seroconversion rates between groups was above the pre-defined limit of −10.0%. The immune responses remained high for all antigens and well above the level of protection 12 months after vaccination in all groups. There were no safety concerns.

Conclusions

JE-CV is safe and induces a strong protective immune response which persists over 1 year when co-administered with MMR vaccine.     

Immunogenicity and safety of a fully liquid aluminum phosphate adjuvanted Haemophilus influenzae type b PRP-CRM197-conjugate vaccine in healthy Japanese children: A phase III,randomized, observer-blind,multicenter, parallel-group study

BackgroundBroad use of monovalent Haemophilus influenzae type b (Hib) conjugate vaccines based on the capsular polysaccharide polyribosyl-ribitol phosphate (PRP), has significantly reduced invasive Hib disease burden in children worldwide, particularly in children aged <1 year. In Japan, PRP conjugated to tetanus toxoid (PRP-T) vaccine has been widely used since the initiation of public funding programs followed by a routine vaccination designation in 2013.MethodsWe compared the immunogenicity and safety of PRP conjugated to a non-toxic diphtheria toxin mutant (PRP-CRM₁₉₇) vaccine with the PRP-T vaccine when administered subcutaneously to healthy Japanese children in a phase III study. Additionally, we evaluated the immunogenicity and safety profiles of a diphtheria–tetanus acellular pertussis (DTaP) combination vaccine when concomitantly administered with either PRP-CRM₁₉₇ or PRP-T vaccines. The primary endpoint was the “long-term seroprotection rate”, defined as the group proportion with anti-PRP antibody titers ⩾1.0 μg/mL, after the primary series.ResultsLong-term seroprotection rates were 99.3% in the PRP-CRM₁₉₇ group and 95.6% in the PRP-T group. The intergroup difference (PRP-CRM₁₉₇ group – PRP-T group) was 3.7% (95% confidence interval: 0.099–7.336), demonstrating that PRP-CRM₁₉₇ vaccine was non-inferior to PRP-T vaccine (p < 0.0001). Furthermore, the “short-term seroprotection rate” (anti-PRP antibody titer ⩾0.15 μg/mL) before booster vaccination was higher in the PRP-CRM₁₉₇ group than in PRP-T. Concomitant administration of PRP-CRM₁₉₇ vaccine with DTaP vaccine showed no differences in terms of immunogenicity compared with concomitant vaccination with PRP-T vaccine and DTaP vaccine. Although CRM₁₉₇ vaccine had higher local reactogenicity, overall, both Hib vaccines had acceptable safety and tolerability profiles.ConclusionThe immunogenicity of PRP-CRM₁₉₇ vaccine administered subcutaneously as a three-dose primary series in children followed by a booster vaccination 1 year after the primary series induced protective levels of Hib antibodies with no safety or tolerability concerns.Clinical trial registry: Registered on ClinicalTrials.gov: NCT01379846     

Influenza vaccines effectiveness 2013–14 through 2015–16, a test-negative study in children

BackgroundTrivalent inactivated and live attenuated influenza vaccines (IIV3 and LAIV3) have been reformulated with an extra B strain (IIV4 and LAIV4). They were licensed based on immunogenicity and their effectiveness (VE) still must be empirically tested.MethodsChildren 1–17 years tested for influenza during 2013–16 were included and their immunization status verified. They were considered vaccinated if received ≥1 dose of an influenza vaccine ≥10 days before evaluated for a respiratory episode. Age-groups were classified as 1–4 years or 5–17 years. VE was estimated by comparing vaccination status of influenza-positive versus influenza-negative cases.Results6779 children were enrolled in the three seasons. Overall, 27.2% received an influenza vaccine (87.1% IIV3 or IIV4 and 12.9% LAIV4), and 15.6% tested positive for influenza (77.9% A). IIV3 was predominantly used in 2013–14 and IIV4 in 2014–15 and 2015–16. IIV3 and IIV4 had comparable VE over the three seasons (60%, 57% and 53%) and performed similarly against influenza A and B and both age-groups. LAIV4 performed poorly for influenza A (15%, 37% and 48%) but better for influenza B (100%, 56% and 100%), especially among children 5–17 years of age with VE = 100% (95%CI: 55, 100).ConclusionsInfluenza vaccination showed modest but consistent effectiveness over the years. The switch from IIV3 to IIV4 did not affect VE. LAIV4 did not perform as well as IIVs, yet it improved over the years and was particularly good protecting older children against influenza B. These results emphasize the regional nature of influenza and the need for local surveillance.     

Reduced schedules of 4CMenB vaccine in infants and catch-up series in children: Immunogenicity and safety results from a randomised open-label phase 3b trial

BackgroundThis study evaluated the immunogenicity and safety of a licensed meningococcal serogroup B vaccine (4CMenB) administered alone according to reduced schedules in infants or catch-up series in children.MethodsIn this open-label, multicentre, phase 3b study (NCT01339923), infants randomised 1:1:1 received 4CMenB: 2 + 1 doses at 3½–5–11 months or 6–8–11 months of age, 3 + 1 doses at ages 2½–3½–5–11 months. Children aged 2–10 years received 2 catch-up doses administered 2 months apart. Immune responses were measured by hSBA assays against 4 strains specific for vaccine components fHbp, NadA, PorA and NHBA. Sufficiency of immune responses was defined in groups with 2 + 1 doses schedules as a lower limit ≥70% for the 97.5% confidence interval of the percentage of infants with hSBA titres ≥4, 1 month post-dose 2 for fHbp, NadA, PorA. Adverse events were collected for 7 days post-vaccination; serious adverse events (SAEs) throughout the study.Results754 infants and 404 children were enrolled. Post-primary vaccination, 98–100% of infants across all groups developed hSBA titres ≥4 for fHbp, NadA, PorA, and 48–77% for NHBA. Sufficiency of immune responses in infants receiving 2 + 1 schedules was demonstrated for fHbp, NadA, PorA after 2 doses of 4CMenB, as pre-specified criteria were met. Following receipt of 2 catch-up doses, 95–99% of children developed hSBA titres ≥4 for 4CMenB components. Similar safety profiles were observed across groups. A total of 45 SAEs were reported, 3 of which were related to vaccination.ConclusionReduced infant schedules and catch-up series in children were immunogenic and safe, having the potential to widen 4CMenB vaccine coverage.FundingGlaxoSmithKline Biologicals SA.     

Influenza vaccine: Delayed vaccination schedules and missed opportunities in children under 2 years old

IntroductionIn Argentina respiratory disease is the third leading cause of death in children under 5 years. In 2011 influenza vaccination was included in the National Calendar for children between 6 and 24 months (two doses schedule). Influenza vaccine coverage for second dose was 46.1% in 2013. The aim was to determine the proportion of delayed schedules and missed opportunities, to assess the characteristics of missed opportunities for vaccination and to explore the perception of influenza disease and vaccination from the parents of children between 6 and 24 months in different regions of Argentina in 2013.MethodsAnalytical observational multicenter cross-sectional study. Structured surveys were carried out to the children's parents who were between 6 and 24 months of age during the influenza virus vaccination season (April–October 2013). Chi-Square test was used to assess association and differences between proportions and categorical variables. A logistic regression model was built to identify delay predictor variables in the vaccination schedules. Missed opportunities for vaccination were characterized through the estimation of proportions.Results1350 surveys were conducted in the three centers. We detected 65% (884/1340) of delayed influenza vaccination schedules, 97% of them associated with missed opportunities of vaccination. The independent protective factors associated with a decreases risk of delayed schedules were: (a) perception of the importance of influenza vaccination (OR = 0.42(0.18–0.94); p = 0.035), (b) having less than one year of age (OR = 0.75(0.59–0.96); p = 0.022), (c) to have received information in pediatric visits or in any media (OR = 0.71(0.56–0.90); p = 0.004). There was 38% of MOIV in 1st dose and 63.4% in 2nd dose. The main cause of MOIV in 1st dose was not detecting the need for vaccination (39%) and in 2nd dose the unknowledge of the vaccination schedule (35.3%). No cultural reasons were detected.ConclusionsHigh frequency of delayed vaccination schedules and missed opportunities were detected. Parents had little concern about the safety of influenza vaccine.     

Primary and booster immune responses to SA14-14-2 Japanese encephalitis vaccine in Korean infants.

Attenuated SA14-14-2 Japanese encephalitis (JE) vaccine has been administered safely and effectively to more than 100 million children in China since 1988 and recently, licensure of the vaccine in Korea has been sought. In the first clinical evaluation of the vaccine outside of China, we monitored side effects in 84 children and evaluated antibody responses to a single dose given as primary JE vaccination in 68 children, 1-3 years old (mean age 27 months). No significant adverse events were noted. Neutralizing antibodies (geometric mean titer [GMT] of 188) were produced in 96% of the 68 subjects. In 10 other children who previously had been immunized with two or three doses of inactivated JE vaccine, the booster administration of SA14-14-2 vaccine produced an anamnestic response in all, with a GMT of 3378. In a comparison group of 25 children previously immunized with two doses of inactivated vaccine, neutralizing antibody titers were detected in 16 (64%). Viral specific IgM was detected in nine primary vaccinees (13%) but in others, IgM may have declined to undetectable levels in the four week postimmunization sample. Live attenuated SA14-14-2 JE vaccine is a promising alternative to the only commercially available JE vaccine for national childhood immunization programs in Asia.     

Antigenic characterization of the live attenuated Japanese encephalitis vaccine virus SA14-14-2: a comparison with isolates of the virus covering a wide geographic area.

In China, a live attenuated Japanese encephalitis (JE) vaccine, based on strain SA14-14-2, has been derived from the wild-type strain SA14 as an alternative to the current inactivated vaccines such as Nakayama-NIH and P-3. SA14-14-2 has been characterized using monoclonal antibodies derived in mice, using HAI and neutralization tests, and compared with other Chinese live vaccine clones and 14 wild-type strains of JE virus. Wild-type strain SA14 was found to be a poor immunogen and antigenically distant from all other viruses examined. The vaccine derivatives SA14-5-3 was more immunogenic than its wild-type parent, while SA14-14-2 (derived from SA14-5-3) was more immunogenic than SA14-5-3 and elicited a cross neutralizing antibody response. Our studies indicated that JE virus strain Nakayama elicited as good a neutralizing antibody response in hyperimmunized mice as the SA14-14-2 vaccine clones grown in either primary hamster kidney (PHK) or primary dog kidney (PDK) cells. A single dose of live SA14-14-2 (PHK) also elicited a good antibody response. Antigenic variation between wild-type and vaccine clones of JE virus were detected but were not considered significant in terms of controlling JE virus infections by vaccination.     

Lot-to-lot consistency,safety and immunogenicity of 3 lots of Haemophilus influenzae type b conjugate vaccine: results from a phase III randomized,multicenter study in infants

BackgroundVaccination against Haemophilus influenzae type b (Hib) is included in routine pediatric immunization schedule in the United States. Previous vaccine shortages have created the need for additional options for Hib vaccination.MethodsThis phase III, randomized, multi-centered study (NCT01000974) evaluated the safety and immunogenicity of a monovalent tetanus toxoid-conjugate Hib vaccine (Hib-TT) compared to a monovalent (Hib-TT control) and a combination Hib-TT vaccine. We hierarchically assessed lot-to-lot consistency of 3 Hib-TT lots and non-inferiority of Hib-TT to Hib-TT control. We co-administered routine pediatric vaccines with Hib-TT vaccines at 2, 4, 6 months (primary vaccination) and 15–18 months of age (booster vaccination). We recorded adverse events (AEs) for 4 (solicited) and 31 days (unsolicited) post-vaccination and serious AEs (SAEs) throughout the study.ResultsOf 4009 enrolled children, 3086 completed booster phase. Lot-to-lot consistency was not demonstrated. The study met statistical criteria for non-inferiority of Hib-TT to Hib-TT control in terms of immune responses to Hib and co-administered vaccines’ antigens, but not in terms of participants achieving post-primary vaccination anti-PRP levels ≥1 µg/mL. Because of the hierarchical nature of the objectives, non-inferiority could not be established. In all groups, 92.5–96.7% and 99.6–100% of participants achieved anti-PRP levels ≥0.15 µg/mL, while 78.3–89.8% and 97.9–99.1% had anti-PRP levels ≥1 µg/mL, post-primary and post-booster vaccination, respectively. Immune responses to co-administered vaccines and reported incidence of AEs were comparable among groups. We recorded SAEs for 107/2963 (3.6%), 24/520 (4.6%), and 21/520 (4.0%) children post-primary vaccination, and 29/2337 (1.2%), 4/435 (0.9%), and 2/400 (0.5%) children post-booster vaccination with Hib-TT, Hib-TT control and combination Hib-TT vaccine, respectively; 6/5330 (0.1%) SAEs in the Hib-TT groups were considered vaccine-related.ConclusionHib-TT induced seroprotective antibody concentrations in the majority of participants and was well-tolerated when co-administered with routine pediatric vaccines according to a 3 + 1 schedule.     

Brief education to promote maternal influenza vaccine uptake: A randomized controlled trial

BackgroundAlthough pregnant women are the highest priority group for seasonal influenza vaccination, maternal influenza vaccination rates remain suboptimal. The purpose of this study was to evaluate the effect of a brief education intervention on maternal influenza vaccine uptake.MethodsDuring the 2013–14 and 2014–15 influenza seasons, we recruited 321 pregnant women from the antenatal clinics of 4 out of 8 public hospitals in Hong Kong with obstetric services. Hospitals were geographically dispersed and provided services to pregnant women with variable socioeconomic backgrounds. Participants were randomized to receive either standard antenatal care or brief one-to-one education. Participants received telephone follow-up at 2 weeks postpartum. The primary study outcome was self-reported receipt of influenza vaccination during pregnancy. The secondary outcomes were the proportion of participants who initiated discussion about influenza vaccination with a health care professional and the proportion of participants who attempted to get vaccinated.ResultsCompared with participants who received standard care, the vaccination rate was higher among participants who received brief education (21.1% vs. 10%; p = 0.006). More participants in the education group initiated discussion about influenza vaccination with their HCP (19.9% vs. 13.1%; p = 0.10), but the difference was not statistically significant. Of participants who did not receive the influenza vaccine (n = 271), 45 attempted to get vaccinated. A significantly higher proportion of participants who attempted to get vaccinated were in the intervention group (82.2% vs. 17.8%; p < 0.001). If participants who had attempted vaccination had received the vaccine, vaccination rates would have been substantially higher (44.1% vs. 15%; p < 0.001). Twenty-six participants were advised against influenza vaccination by a healthcare professional, including general practitioners, obstetricians, and nurses.ConclusionAlthough brief education was effective in improving vaccination uptake among pregnant women, overall vaccination rates remain suboptimal. Multicomponent approaches, including positive vaccination recommendations by healthcare professionals, are needed to promote maternal influenza vaccination.Clinical Trial Registration: www.clinicaltrials.gov (NCT01772901).     

Antibody persistence after serogroup C meningococcal conjugate vaccine in children with sickle cell disease

BackgroundA decline of protective antibody titers after MCC vaccine has been demonstrated in healthy children, this may be an issue of concern for risk groups. The aim of this study was to evaluate the persistence of bactericidal antibodies after MCC vaccine in sickle cell disease (SCD) patients. The type of vaccine used and booster response were also analyzed.MethodsSCD patients (n = 141) previously immunized with MCC vaccines had blood drawn 2–8 years after the last priming dose. They were distributed according to age at primary immunization into groups: <2 years and 2–13 years and evaluated by years since vaccination (2–3, 4–5 and 6–8). Serum bactericidal antibodies with baby rabbit complement (rSBA) and serogroup C-specific IgG concentrations were measured. The correlate of protection was rSBA titer ⩾8. Subjects with rSBA <8 received a booster dose and antibody levels re-evaluated after 4–6 weeks.ResultsFor children primed under 2 years of age rSBA titer ⩾8 was demonstrated in 53.3%, 21.7% and 35.0%, 2–3, 4–5, 6–8 years, respectively, after vaccination, compared with 70.0%, 45.0% and 53.5%, respectively, for individuals primed at ages 2–13 years. rSBA median titers and IgG median levels were higher in the older group. Six to eight years after vaccination the percentage of patients with rSBA titers ⩾8 was significantly higher in the group primed with MCC-TT (78.5%) compared with those primed with MCC-CRM₁₉₇ [Menjugate® (33.3%) or Meningitec® (35.7%)] (p = 0.033). After a booster, 98% achieved rSBA titer ⩾8.ConclusionImmunity to meningococcal serogroup C in SCD children declines rapidly after vaccination and is dependent on the age at priming. Booster doses are needed to maintain protection in SCD patients. Persistence of antibodies seems to be longer in individuals primed with MCC-TT vaccine comparing to those immunized with MCC-CRM₁₉₇.     

From current vaccine recommendations to everyday practices: An analysis in five sub-Saharan African countries

BackgroundEstimates of WHO and UNICEF vaccination coverage may provide little insight into the extent to which vaccinations are administered on time. Yet, lack of adherence to the recommended age to receive a specific vaccination may have detrimental health consequences. For example, delays in receiving vaccination will prolong the risk of lack of protection, often when disease risk is highest, such as during early infancy. We estimated the reported age at vaccination, and vaccine coverage at different ages in children from five sub-Saharan African countries.MethodsWe analyzed data from the latest Demographic and Health Programme databases available for Burkina Faso 2010 (n = 15,044 observations), Ghana 2008 (n = 2992), Kenya 2008–9 (n = 6079), Senegal 2010–11 (n = 12,326), and Tanzania 2010 (n = 8023). We assessed, amongst vaccinees, the exact age when vaccine was administered for the three infant doses of pentavalent vaccine (DTP) and the first dose of measles-containing-vaccine (MCV), as well as the proportion of children immunized with these antigens by a certain age. Vitamin A supplementation (VAS) coverage was evaluated as a potential contact visit for vaccine introduction.ResultsFor all DTP doses, the median intervals between recommended and actual ages of receiving vaccination ranged from 12, 17 and 23 days in Kenya, to 22, 33 and 45 days in Senegal. MCV was mostly given during the recommended age of 9 months. In each country, there was a large discrepancy in the median age at DTP vaccination between regions. VAS coverage in young children ranged from 30.3% in Kenya to 78.4% in Senegal, with large variations observed between areas within each study country.ConclusionIn the context of new vaccine introduction, age of children at vaccination should be monitored to interpret data on vaccine-preventable disease burden, vaccine effectiveness, and vaccine safety, and to adapt targeted interventions and messages.