Effect of booster doses of poliovirus vaccine in previously vaccinated children,Clinical Trial Results 2013

BackgroundConsidering the current polio situation Pakistan needs vaccine combinations to reach maximum population level immunity. The trial assessed whether inactivated poliovirus vaccine (IPV) can be used to rapidly boost immunity among children in Pakistan.MethodsA five-arm randomized clinical trial was conducted among children (6–24 months, 5–6 years and 10–11 years). Children were randomized in four intervention arms as per the vaccines they received (bOPV, IPV, bOPV + vitamin A, and bOPV + IPV) and a control arm which did not receive any vaccine. Baseline seroprevalence of poliovirus antibodies and serological immune response 28 days after intervention were assessed.ResultsThe baseline seroprevalence was high for all serotypes and the three age groups [PV1: 97%, 100%, 96%, PV2: 86%, 100%, 99%, PV3: 83%, 95%, 87% for the three age groups respectively]. There was significantly higher rate of immune response observed in the study arms which included IPV (95–99%) compared with bOPV only arms (11–43%), [p < 0.001]; Vitamin A was not associated with improved immune response. Immune response rates in the IPV only arm and IPV + bOPV arm were similar [p > 0.5].ConclusionIPV has shown the ability to efficiently close existing immunity gaps in a vulnerable population of children in rural Pakistan.     

Effect of multiple,simultaneous vaccines on polio seroresponse and associated health outcomes

BackgroundAdministration of multiple simultaneous vaccines to infants, children, and military recruits is not uncommon. However, little research exists to examine associated serological and health effects, especially in adults.MethodWe retrospectively examined 416 paired serum specimens from U.S. military subjects who had received the inactivated polio vaccine (IPV) alone or in combination with either 1 other vaccine (<3 group) or 4 other vaccines (>4 group). Each of the 2 groups was subdivided into 2 subgroups in which Tdap was present or absent.ResultsThe >4 group was associated with a higher proportion of polio seroconversions than the <3 group (95% vs. 58%, respectively, p < 0.01). Analysis of the <3 subgroup that excluded Tdap vs. the >4 subgroup that excluded Tdap showed no difference between them (p > 0.1). However, the >4 subgroup that included Tdap had significantly more seroconversions than either the <3 subgroup that excluded Tdap or the >4 subgroup that excluded Tdap (p < 0.01). Overall, at least 98% of subjects were at or above the putative level of seroprotection both pre- and post-vaccination, yet at least 81% of subjects seroconverted. In an analysis of 400 of the subjects in which clinic in- and outpatient encounters were counted over the course of 1 year following vaccinations, there was no significant difference between the 2 groups (p > 0.1).ConclusionA combination of >4 vaccines including IPV appeared to have an immunopotentiation effect on polio seroconversion, and Tdap in particular was a strong candidate for an important role. The dose of IPV we studied in our subjects, who already had a high level of seroprotection, acted as a booster. In addition, there appear to be no negative health consequences from receiving few versus more multiple simultaneous vaccinations.     

Immunogenicity and persistence from different 3-dose schedules of live and inactivated polio vaccines in Chinese infants

BackgroundOPV is the only poliovirus vaccine used in the China EPI system, although IPV is available in the private market. We compared immunigencity and persistence among different schedules of IPV and OPV.Methods536 Chinese infants were enrolled into 4 groups receiving different schedules administered at 2, 3, and 4 months of age: IPV–OPV–OPV, IPV–IPV–OPV, IPV–IPV–IPV, and OPV–OPV–OPV. The I–I–I group received an 18-month IPV booster dose. Blood samples were collected before the first dose, after the third dose, and at 18 months for all groups, and also after the booster dose for the I–I–I group. Polio neutralizing antibody titers were assessed, and seroprotection rates were calculated after primary immunization and at 18 months of age.ResultsBefore the first dose, GMTs of the 4 groups ranged from 2.96 to 6.89, and seroprotection rates ranged from 17.6% to 54.3%. After 3 doses, the GMT of the I–O–O and I–I–O groups ranged from 901.09 to 1,110.12, and the GMT of the I–I–I group range was 212.02 to 537.52, significantly lower than for the 2 sequential schedules (P < 0.001). Seroprotection rates were 98.1% to 100%, with no significant differences among groups. At 18 months of age, the GMTs declined to a range of 527.00 to 683.44 in the I–O–O and I–I–O groups, and declined to 150.04 to 239.89 in the I–I–I group, significantly lower than for the other 3 groups (P < 0.001).ConclusionsThe sequential schedules achieved high GMTs and seroprotection. The IPV-only schedule achieved high seroprotection but with lower GMTs. Sequential schedules are suitable for China. With the 2 sequential schedules, GMTs remained high at 18 months of age and were not inferior to the OPV-only schedule. Thus, with a sequential schedule, the booster dose could be given at 4 years of age, the same age as the current OPV booster dose.     

Acquisition of Streptococcus pneumoniae in South African children vaccinated with 7-valent pneumococcal conjugate vaccine at 6, 14 and 40 weeks of age

BackgroundSeven-valent pneumococcal conjugate vaccine (PCV7) was introduced into the South African immunization program using 6, 14 and 40 weeks dosing schedule (2 + 1), with no catch-up in older children since April 2009. We investigated pneumococcal colonization acquisition in children who received this schedule and also compared it to historical cohorts of PCV-naïve children (n = 123 in 2007) and children who received a 3 + 1 PCV7 schedule (n = 124 in 2005/06).MethodsTwo hundred and fifty children aged 6–12 weeks were enrolled from December 2009 to April 2010. Participants had nasopharyngeal swabs collected on eight occasions between enrolment and 2-years of age. Standard methods were undertaken for bacterial culture and Streptococcus pneumoniae were serotyped using the Quellung method. Pneumococcal and Staphylococcus aureus colonization in the present study was compared to colonization in two historical longitudinal cohorts.ResultsS. pneumoniae was identified in 1081 (61.4%) of 1761 swabs collected in the current cohort. Pneumococcal colonization peaked at 41-weeks of age (76.8%) and decreased to 62.8% by 2-years of age (p = 0.002); PCV7-serotype colonization decreased during the same period from 28.6% to 15.6% (p = 0.001). Children from the current cohort compared to PCV-naïve children were less likely to be colonized by PCV7-serotypes from 40-weeks to 2-years of age and acquired PCV7-serotypes less frequently. No differences in overall pneumococcal, PCV7-serotype and non-PCV7-serotype colonization or new serotype acquisitions were detected comparing the current cohort to the historical cohort who received the 3 + 1 PCV7 schedule. Staphylococcus aureus colonization was similar in all three cohorts.ConclusionA 2 + 1 PCV7 schedule implemented in South Africa was temporally associated with reduced risk of vaccine-serotype colonization compared to historically unvaccinated children. Also, vaccine-serotype acquisition rate using the 2 + 1 schedule was similar to that in the 3 + 1 dosing cohort, suggesting that similar indirect protection against pneumococcal disease could be derived from either schedule in South Africa.     

Is there an association between the coverage of immunisation boosters by the age of 5 and deprivation? An ecological study

ObjectiveTo determine whether there was an association between the coverage of booster immunisation of Diphtheria, Tetanus, acellular Pertussis and Polio (DTaP/IPV) and second Measles, Mumps and Rubella (MMR) dose by age 5 in accordance with the English national immunisation schedule by area-level socioeconomic deprivation and whether this changed between 2007/08 and 2010/11.DesignEcological study.DataRoutinely collected national Cover of Vaccination Evaluated Rapidly data on immunisation coverage for DTaP/IPV booster and second MMR dose by age 5 and the Index of Multiple Deprivation (IMD).SettingPrimary Care Trust (PCT) areas in England between 2007/08 and 2010/11.Outcome MeasuresPopulation coverage (%) of DTaP/IPV booster and second MMR immunisation by age 5.ResultsOver the 4 years among the 9,457,600 children there was an increase in the mean proportion of children being immunised for DTaP/IPV booster and second MMR across England, increasing from 79% (standard deviation (SD12%)) to 86% (SD8%) for DTaP/IPV and 75% (SD10%) to 84% (SD6%) for second MMR between 2007/08 and 2010/11. In 2007/08 the area with lowest DTaP/IPV booster coverage was 31% compared to 54.4% in 2010/11 and for the second MMR in 2007/08 was 39% compared to 64.8% in 2010/11. A weak negative correlation was observed between average IMD score and immunisation coverage for the DTaP/IPV booster which reduced but remained statistically significant over the study period (r = −0.298, p < 0.001 in 2007/08 and r = −0.179, p = 0.028 in 2010/11). This was similar for the second MMR in 2007/08 (r = −0.225, p = 0.008) and 2008/09 (r = −0.216, p = 0.008) but there was no statistically significant correlation in 2009/10 (r = −0.108, p = 0.186) or 2010/11 (r = −0.078, p = 0.343).ConclusionLower immunisation coverage of DTaP/IPV booster and second MMR dose was associated with higher area-level socioeconomic deprivation, although this inequality reduced between 2007/08 and 2010/11 as proportions of children being immunised increased at PCT level, particularly for the most deprived areas. However, coverage is still below the World Health Organisation recommended 95% threshold for Europe.     

Immunogenicity to poliovirus type 2 following two doses of fractional intradermal inactivated poliovirus vaccine: A novel dose sparing immunization schedule

IntroductionThe polio eradication endgame strategic plan calls for the sequential removal of Sabin poliovirus serotypes from the trivalent oral poliovirus vaccine (tOPV), starting with type 2, and the introduction of ≥1 dose of inactivated poliovirus vaccine (IPV), to maintain an immunity base against poliovirus type 2. The global removal of oral poliovirus type 2 was successfully implemented in May 2016. However, IPV supply constraints has prevented introduction in 21 countries and led to complete stock-out in >20 countries.MethodsWe conducted a literature review and contacted corresponding authors of recent studies with fractional-dose IPV (fIPV), one-fifth of intramuscular dose administered intradermally, to conduct additional type 2 immunogenicity analyses of two fIPV doses compared with one full-dose IPV.ResultsFour studies were identified that assessed immunogenicity of two fIPV doses compared to one full-dose IPV. Two fractional doses are more immunogenic than 1 full-dose, with type 2 seroconversion rates improving between absolute 19–42% (median: 37%, p < 0.001) and relative increase of 53–125% (median: 82%), and antibody titer to type 2 increasing by 2–32-fold (median: 10-fold). Early age of administration and shorter intervals between doses were associated with lower immunogenicity.DiscussionOverall, two fIPV doses are more immunogenic than a single full-dose, associated with significantly increased seroconversion rates and antibody titers. Two fIPV doses together use two-fifth of the vaccine compared to one full-dose IPV. In response to the current IPV shortage, a schedule of two fIPV doses at ages 6 and 14 weeks has been endorsed by technical oversight committees and has been introduced in some affected countries.     

The novel adjuvant dmLT promotes dose sparing,mucosal immunity and longevity of antibody responses to the inactivated polio vaccine in a murine model

One option for achieving global polio eradication is to replace the oral poliovirus vaccine (OPV), which has the risk of reversion to wild-type virulence, with the inactivated poliovirus vaccine (IPV) vaccine. Adjuvants and alternate routes of immunization are promising options that may reduce antigen dose in IPV vaccinations, potentially allowing dose sparing and cost savings. Use of adjuvants and alternate routes of immunization could also help promote mucosal immunity, potentially mimicking the protection against intestinal virus shedding seen with OPV. In the current study, we examined the impact of combining the novel adjuvant dmLT with trivalent IPV for dose sparing, induction of mucosal immunity and increasing longevity of anti-poliovirus (PV) responses in a mouse model following either intradermal (ID) or intramuscular (IM) delivery.We found that non-adjuvanted ID delivery was not superior to IM delivery for fractional dose sparing, but was associated with development of mucosal immunity. Vaccination with IPV + dmLT promoted serum anti-PV neutralizing antibodies with fractional IPV doses by either IM or ID delivery, achieving at least five-fold dose sparing above non-adjuvanted fractional doses. These responses were most noticeable with the PV1 component of the trivalent vaccine. dmLT also promoted germinal center formation and longevity of serum anti-PV neutralizing titers. Lastly, dmLT enhanced mucosal immunity, as defined by fecal and intestinal anti-PV IgA secretion, when included in IPV immunization by ID or IM delivery. These studies demonstrate that dmLT is an effective adjuvant for either IM or ID delivery of IPV. Inclusion of dmLT in IPV immunizations allows antigen dose sparing and enhances mucosal immunity and longevity of anti-PV responses.     

The effect of diarrheal disease on bivalent oral polio vaccine (bOPV) immune response in infants in Nepal

BackgroundA globally-coordinated phase out of all type 2 containing oral polio vaccine (OPV) is planned for April 2016 during which bivalent 1 + 3 OPV (bOPV) will replace trivalent OPV (tOPV) in routine immunization schedules and campaigns. Diarrhea impairs the immune response to tOPV, but the effect of diarrhea on bOPV is unknown.MethodsInfants aged 6 weeks to 11 months, who had received <3 doses of OPV and had mild-moderate diarrhea or no diarrhea, were recruited at five health facilities in Nepal. Neutralizing antibody titers to poliovirus types 1 and 3 were measured before and 28 days after bOPV administration. The effect of diarrhea and other factors on seroconversion or boosting in antibody titers to poliovirus was assessed by multivariable analysis.ResultsInfants with diarrhea, versus those without diarrhea, had reduced response for poliovirus types 1 (56% [87/156] vs 66% [109/164]) and 3 (34% [70/209] vs 52% [122/236]). After adjusting for other factors, infants with diarrhea had significantly reduced response for type 3 (odds ratio [OR] = 0.44, 95% CI 0.29–0.68), as did infants with >5 loose stools per day (OR = 0.36, 95% CI 0.21–0.62).ConclusionsDiarrhea reduced the immune response to bOPV. Provision of additional doses of polio vaccine is necessary to maintain high population immunity in areas with high prevalence of diarrheal disease.Clinical trial registryThis study is registered at clinicaltrials.gov as NCT01559636.     

Safety,tolerability, and immunogenicity of inactivated poliovirus vaccine with or without E.coli double mutant heat-labile toxin (dmLT) adjuvant in healthy adults; a phase 1 randomized study

BackgroundInactivated trivalent poliovirus vaccine (IPV) induces humoral immunity, which protects against paralytic poliomyelitis but does not induce sufficient mucosal immunity to block intestinal infection. We assessed the intestinal immunity in healthy adults in Belgium conferred by a co-formulation of IPV with the mucosal adjuvant double mutant Labile Toxin (dmLT) derived from Escherichia coli.MethodsHealthy fully IPV-vaccinated 18–45-year-olds were randomly allocated to three groups: on Day 1 two groups received one full dose of IPV (n = 30) or IPV + dmLT (n = 30) in a blinded manner, and the third received an open-label dose of bivalent live oral polio vaccine (bOPV types 1 and 3, n = 20). All groups received a challenge dose of bOPV on Day 29. Participants reported solicited and unsolicited adverse events (AE) using study diaries. Mucosal immune responses were measured by fecal neutralization and IgA on Days 29 and 43, with fecal shedding of challenge viruses measured for 28 days. Humoral responses were measured by serum neutralizing antibody (NAb).ResultsSolicited and unsolicited AEs were mainly mild-to-moderate and transient in all groups, with no meaningful differences in rates between groups. Fecal shedding of challenge viruses in both IPV groups exceeded that of the bOPV group but was not different between IPV and IPV + dmLT groups. High serum NAb responses were observed in both IPV groups, alongside modest levels of fecal neutralization and IgA.ConclusionsAddition of dmLT to IPV administered intramuscularly neither affected humoral nor intestinal immunity nor decreased fecal virus shedding following bOPV challenge. The tolerability of the dose of dmLT used in this study may allow higher doses to be investigated for impact on mucosal immunity.Registered on ClinicalTrials.gov - NCT04232943.     

Needle adapters for intradermal administration of fractional dose of inactivated poliovirus vaccine: Evaluation of immunogenicity and programmatic feasibility in Pakistan

Administration of 1/5th dose of Inactivated poliovirus vaccine intradermally (fIPV) provides similar immune response as full-dose intramuscular IPV, however, fIPV administration with BCG needle and syringe (BCG NS) is technically difficult. We compared immune response after one fIPV dose administered with BCG NS to administration with intradermal devices, referred to as Device A and B; and assessed feasibility of conducting a door-to-door vaccination campaign with fIPV. In Phase I, 452 children 6–12 months old from Karachi were randomized to receive one fIPV dose either with BCG NS, Device A or Device B in a health facility. Immune response was defined as seroconversion or fourfold rise in polio neutralizing antibody titer 28 days after fIPV among children whose baseline titer ≤362. In Phase II, fIPV was administered during one-day door-to-door campaign to assess programmatic feasibility by evaluating vaccinators’ experience. For all three poliovirus (PV) serotypes, the immune response after BCG NS and Device A was similar, however it was lower with Device B (34/44 (77%), 31/45 (69%), 16/30 (53%) respectively for PV1; 53/78 (68%), 61/83 (74%), 42/80 (53%) for PV2; and; 58/76 (76%), 56/80 (70%), 43/77 (56%) for PV3; p < 0.05 for all three serotypes). Vaccinators reported problems filling Device B in both Phases; no other operational challenges were reported during Phase II. Use of fIPV offers a dose-saving alternative to full-dose IPV.     

Evaluation of vaccine derived poliovirus type 2 outbreak response options: A randomized controlled trial,Karachi, Pakistan

BackgroundOutbreaks of circulating vaccine derived polioviruses type 2 (cVDPV2) remain a risk to poliovirus eradication in an era without live poliovirus vaccine containing type 2 in routine immunization. We evaluated existing outbreak response strategies recommended by the World Health Organization (WHO) for control of cVDPV2 outbreaks.MethodsSeronegative children for poliovirus type 2 (PV2) at 22 weeks of life were assigned to one of four study groups and received respectively (1) one dose of trivalent oral poliovirus vaccine (tOPV); (2) monovalent OPV 2 (mOPV2); (3) tOPV together with a dose of inactivated poliovirus vaccine (IPV); or (4) mOPV2 with monovalent high-potency IPV type 2. Stool and blood samples were collected and assessed for presence of PV2 (stool) and anti-polio antibodies (sera).ResultsWe analyzed data from 265 children seronegative for PV2. Seroconversion to PV2 was achieved in 48, 76, 98 and 100% in Groups 1–4 respectively. mOPV2 was more immunogenic than tOPV alone (p < 0.001); and OPV in combination with IPV was more immunogenic than OPV alone (p < 0.001). There were 33%, 67%, 20% and 43% PV2 excretors in Groups 1–4 respectively. mOPV2 resulted in more prevalent shedding of PV2 than when tOPV was used (p < 0.001); and tOPV together with IPV resulted in lower excretion of PV2 than tOPV alone (p = 0.046).ConclusionmOPV2 was a more potent vaccine than tOPV. Adding IPV to OPV improved immunological response; adding IPV also seemed to have shortened the duration of PV2 shedding. mIPV2 did not provide measurable improvement of immune response when compared to conventional IPV. WHO recommendation to use mOPV2 as a vaccine of first choice in cVDPV2 outbreak response was supported by our findings.Clinical Trial registry number: NCT02189811.     

Oral and fecal polio vaccine excretion following bOPV vaccination among Israeli infants

IntroductionInactivated polio virus (IPV) vaccinations are a mainstay of immunization schedules in developed countries, while oral polio vaccine (OPV) is administered in developing countries and is the main vaccine in outbreaks. Due to circulating wild poliovirus (WPV1) detection in Israel (2013), oral bivalent polio vaccination (bOPV) was administered to IPV primed children and incorporated into the vaccination regimen.ObjectivesWe aimed to determine the extent and timeframe of fecal and salivary polio vaccine virus (Sabin strains) shedding following bOPV vaccination among IPV primed children.MethodsFecal samples were collected from a convenience sample of infants and toddlers attending 11 Israeli daycare centers. Salivary samples were collected from infants and toddlers following bOPV vaccination.Results398 fecal samples were collected from 251 children (ages: 6–32 months), 168 received bOPV vaccination 4–55 days prior to sample collection. Fecal excretion continued among 80 %, 50 %, and 20 %, 2, 3, and 7 weeks following vaccination. There were no significant differences in the rate and duration of positive samples among children immunized with 3 or 4 IPV doses. Boys were 2.3-fold more likely to excrete the virus (p = 0.006). Salivary shedding of Sabin strains occurred in 1/47 (2 %) and 1/49 (2 %) samples 4, and 6 days following vaccination respectively.ConclusionsFecal detection of Sabin strains among IPV-primed children continues for 7 weeks; additional doses of IPV do not augment intestinal immunity; limited salivary shedding occurs for up to a week. This data can enhance understanding of intestinal immunity achieved by different vaccination schedules and guide recommendations for contact precautions of children following bOPV vaccination.     

Safety of Russian-backbone seasonal trivalent,live-attenuated influenza vaccine in a phase II randomized placebo-controlled clinical trial among children in urban Bangladesh

IntroductionLive-attenuated influenza vaccines (LAIVs) have the potential to be affordable, effective, and logistically feasible for immunization of children in low-resource settings.Material and methodsWe conducted a phase II, randomized, double-blind, parallel group, placebo-controlled trial on the safety of the Russian-backbone, seasonal trivalent LAIV among children aged 24 through 59 months in Dhaka, Bangladesh in 2012. After vaccination, we monitored participants for six months with weekly home visits and study clinic surveillance for solicited and unsolicited adverse events, protocol-defined wheezing illness (PDWI), and serious adverse events (SAEs), including all cause hospitalizations.ResultsThree hundred children were randomized and administered LAIV (n = 150) or placebo (n = 150). No immediate post-vaccination reactions occurred in either group. Solicited reactions were similar between vaccine and placebo groups during the first 7 days post-vaccination and throughout the entire trial. There were no statistically significant differences in participants experiencing PDWI between LAIV and placebo groups throughout the trial (n = 13 vs. n = 16, p = 0.697). Of 131 children with a history of medical treatment or hospitalization for asthma or wheezing at study entry, 65 received LAIV and 66 received placebo. Among this subset, there was no statistical difference in PDWI occurring throughout the trial between the LAIV or placebo groups (7.7% vs. 19.7%, p = 0.074). While there were no related SAEs, LAIV recipients had six unrelated SAEs and placebo recipients had none. These SAEs included three due to traumatic injury and bone fracture, and one each due to accidental overdose of paracetamol, abdominal pain, and acute gastroenteritis. None of the participants with SAEs had laboratory-confirmed influenza, wheezing illness, or other signs of acute respiratory illness at the time of their events.ConclusionsIn this randomized, controlled trial among 300 children aged 24 through 59 months in urban Bangladesh, Russian-backbone LAIV was safe and well tolerated. Further evaluation of LAIV safety and efficacy in a larger cohort is warranted.     

Immune response to pneumococcal conjugate vaccine in patients with systemic vasculitis receiving standard of care therapy

AimTo study the effect of standard of care therapy on antibody response and functionality following immunization with 13-valent pneumococcal conjugate vaccine (PCV13) in patients with primary systemic vasculitis compared to healthy controls.Methods49 patients with vasculitis and 49 controls received a single dose (0.5 ml) PCV13 intramuscularly. Ongoing treatments: azathioprine (AZA; n = 11), cyclophosphamide (CYC; n = 6), methotrexate (MTX; n = 9), rituximab (n = 3); anti-TNF (n = 2), mycophenolate mofetil (n = 2), prednisolone alone (n = 15) and no active treatment (n = 2). Specific antibody concentrations for serotypes 6B and 23F were determined using ELISA and opsonophagocytic activity (OPA) assay (23F) was performed, on serum samples taken immediately before and 4–6 weeks after vaccination. Proportion of individuals with putative protective antibody concentration (≥1.0 µg/mL) and positive antibody response (≥2-fold increase from prevaccination concentration) for both serotypes were calculated and groups were compared.ResultsAt baseline, 6 patients (12%) and 12 controls (24%) had protective antibody levels for both serotypes. After vaccination, antibodies increased for both serotypes in patients and controls (p < 0.001), 32 patients (65%) and 35 controls (71%) reached protective level for 6B, and 32 patients (65%) and 37 controls (76%) for 23 F. Compared to controls, patients had lower prevaccination geometric mean concentration (23F, p = 0.01) and a numerical trend towards lower prevaccination level (6B) and postvaccination levels (both serotypes). Patients with prednisolone alone had lower prevaccination OPA (p < 0.01) compared to controls. OPA increased after vaccination in both patients and controls (p < 0.001), but improvement was better in controls (p = 0.001). AZA, CYC or MTX, but not prednisolone alone, tended towards a lower proportion of patients reaching protective antibody levels (p = 0.06), compared to controls.ConclusionsPneumococcal conjugate vaccine was safe and immunogenic in patients with established vasculitis. Treatment with DMARDs, mostly AZA, CYC and MTX but not systemic prednisolone may impair antibody response.Trial registration. ClinicalTrials.gov Identifier: NCT02240888. Registered 4 September, 2014     

Inactivated polio vaccines from three different manufacturers have equivalent safety and immunogenicity when given as 1 or 2 additional doses after bivalent OPV: Results from a randomized controlled trial in Latin America

BackgroundSince April 2016 inactivated poliovirus vaccine (IPV) has been the only routine source of polio type 2 protection worldwide. With IPV supply constraints, data on comparability of immunogenicity and safety will be important to optimally utilize available supplies from different manufacturers.MethodsIn this multicenter phase IV study, 900 Latin American infants randomly assigned to six study groups received three doses of bOPV at 6, 10 and 14 weeks and either one IPV dose at 14 weeks (groups SP-1, GSK-1 and BBio-1) or two IPV doses at 14 and 36 weeks (groups SP-2, GSK-2 and BBio-2) from three different manufacturers. Children were challenged with mOPV2 at either 18 (one IPV dose) or 40 weeks (two IPV doses) and stools were collected weekly for 4 weeks to assess viral shedding. Serum neutralizing antibodies were measured at various time points pre and post vaccination. Serious adverse events and important medical events (SAE and IME) were monitored for 6 months after last study vaccine.ResultsAt week 18, 4 weeks after one dose of IPV, overall type 2 seroconversion rates were 80.4%, 80.4% and 73.3% for SP-1, GSK-1 and BBio-1 groups, respectively; and 92.6%, 96.8% and 88.0% in those who were seronegative before IPV administration. At 40 weeks, 4 weeks after a second IPV dose, type 2 seroconversion rates were ≥99% for any of the three manufacturers. There were no significant differences in fecal shedding index endpoint (SIE) after one or two IPV doses (SP: 2.3 [95% CI: 2.1–2.6]); GSK: 2.2 [1.7–2.5]; BBio 1.8 [1.5–2.3]. All vaccines appeared safe, with no vaccine-related SAE or IME.ConclusionCurrent WHO prequalified IPV vaccines are safe and induce similar humoral and intestinal immunity after one or two doses.The parent study was registered with ClinicalTrials.gov, number NCT01831050.     

Carriage prevalence and serotype distribution of Streptococcus pneumoniae prior to 10-valent pneumococcal vaccine introduction: A population-based cross-sectional study in South Western Uganda, 2014

BackgroundInformation on Streptococcus pneumoniae nasopharyngeal (NP) carriage before the pneumococcal conjugate vaccine (PCV) introduction is essential to monitor impact. The 10-valent PCV (PCV10) was officially introduced throughout Ugandan national childhood immunization programs in 2013 and rolled-out countrywide during 2014. We aimed to measure the age-specific Streptococcus pneumoniae carriage and serotype distribution across all population age groups in the pre-PCV10 era in South Western Uganda.MethodsWe conducted a two-stage cluster, age-stratified, cross-sectional community-based study in Sheema North sub-district between January and March 2014. One NP swab was collected and analyzed for each participant in accordance with World Health Organization guidelines.ResultsNP carriage of any pneumococcal serotype was higher among children <2 years old (77%; n = 387) than among participants aged ≥15 years (8.5%; n = 325) (chi² p < 0.001).Of the 623 positive cultures, we identified 49 serotypes among 610 (97.9%) isolates; thirteen (2.1%) isolates were non-typeable. Among <2 years old, serotypes 6A, 6B, 14, 15B, 19F and 23F accounted for half of all carriers. Carriage prevalence with PCV10 serotypes was 29.4% among individuals aged <2 years (n = 387), 23.4% in children aged 2–4 years (n = 217), 11.4% in 5–14 years (n = 417), and 0.4% among individuals ≥15 years of age (n = 325). The proportion of carried pneumococci serotypes contained in PCV10 was 38.1% (n = 291), 32.8% (n = 154), 29.4% (n = 156), and 4.4% (n = 22) among carriers aged <2 years, 2–4 years, 5–14 years and ≥15 years, respectively.DiscussionIn Sheema district, the proportion of PCV10 serotypes was low (<40%), across all age groups, especially among individuals aged 15 years or older (<5%). PCV10 introduction is likely to impact transmission among children and to older individuals, but less likely to substantially modify pneumococcal NP ecology among individuals aged 15 years or older.     

Four-year persistence of type-specific immunity after quadrivalent human papillomavirus vaccination in HIV-infected children: Effect of a fourth dose of vaccine

ObjectiveAlthough HIV-infected children are recommended to receive quadrivalent human papillomavirus vaccine (QHPV) there is limited information on their response to QHPV. This study in HIV-infected children, evaluated the magnitude and duration of immune responses to QHPV. This report describes type-specific serum antibody responses over a 4-to-5 year period after either 3 or 4 doses of QHPV.Design/methodsHIV-infected children, ages 7-to-11 years, received 3 doses of QHPV (n = 96) or placebo (n = 30). At 72 weeks QHPV recipients received a fourth dose (n = 84), while placebo recipients began the 3-dose QHPV schedule (n = 27). HPV serotype-specific antibody was determined, by competitive Luminex immunoassay (cLIA) and IgG Luminex immunoassay, at 2, 3.5, and 4-to-5 years after the last dose of QHPV in each treatment arm.ResultsAt 4-to-5 years after the last dose of QHPV, antibody titers were significantly higher in 4-dose than in 3-dose group. However, the proportion of vaccinees with a seroresponse in the cLIA assay was not different between the two groups (86–93% for HPV types 6, 11, and 16, and 64% for HPV type 18). These results were very similar to the seroresponse rate in these HIV-infected children at 1 month after completing vaccination.ConclusionsChildren with well-controlled HIV infection who receive 3 doses of the QHPV vaccine maintain seropositivity and antibody levels that are generally similar to children of the same age who are not HIV-infected. Antibody titer correlated strongly with low log HIV RNA, low CD8%, and high CD4%. Additionally, a fourth dose of vaccine in HIV-infected children produces a marked rise in antibody characteristic of an anamnestic response and persistence of high antibody levels.Study identification: IMPAACT P1085 (V501-021). CLINICALTRIALS.GOV identifier: NCT01206556.     

Rapid impact of rotavirus vaccine introduction to the National Immunization Plan in Southern Israel: Comparison between 2 distinct populations

BackgroundRotavirus vaccines were licensed in Israel in 2007, and in 2011 the pentavalent-vaccine (RV5) was introduced into the Israeli National Immunization plan.AimTo determine the effect of rotavirus-vaccines on the incidence of hospital visits due to rotavirus gastroenteritis (RVGE) and all-cause diarrhea in Jewish and Bedouin children <5 year residing in southern Israel.MethodsWe conducted a population-based, prospective, observational study. Data from 2006 through 2013 were analyzed. Our hospital is the only medical center in the region, enabling age-specific incidences calculation.ResultsIn the pre-vaccine period, the overall RVGE hospital visits rates per 1000 in children <12, 12–23 and 24–59 m were 16.1, 18.6 and 1.4 in Jewish children, respectively. The respective rates in Bedouin children were 26.4, 12.5 and 0.7 (P < 0.001 for <12 m).Hospitalization rates were higher among Bedouin than among Jewish children (60.0% vs. 39.7%, P < 0.001). Vaccine uptake was faster in the Jewish vs. the Bedouin population.In the year following RV5 introduction, RVGE hospital visits rates declined by 82%, 70% (P < 0.001 both) and 36% (P = 0.092) in Jewish children <12, 12–23 and 24–59 m, respectively. In Bedouin children, the respective RVGE rates declined by 70% (P < 0.001), 21% (P = ns) and 14% (P = ns).Throughout the study, RVGE rates declined significantly in children <12, and 12–23 m by 80% and 88% in Jewish children, respectively, and by 62 and 75% in Bedouin children, respectively (P < 0.001 for all declines). In children 24–59 m, RVGE rates declined by 46% (P = 0.025) in Jewish children, but no reduction was observed in Bedouin children. The dynamics of all-cause diarrhea rates were similar to that of RVGE.ConclusionsSignificant reductions of RVGE rates were observed, following Rota-vaccine introduction in southern Israel in both Jewish and Bedouin children. However, the impact was faster and more profound in Jewish children, probably related to higher vaccine uptake and possibly to lifestyle differences.     

Frequency of complications and the effects of pneumococcal vaccination in young children with acute respiratory tract infection

BackgroundAcute respiratory infection (ARI) is the most frequent reason for children being seen by doctors worldwide. We aimed to estimate the frequency of complications in children aged 6–23 months during ARI episode and to evaluate risk factors present on recruitment associated with complications after the universal implementation of pneumococcal vaccine (PCV10) in our region.MethodsThis prospective cohort enrolled children who had shown ARI for up to 7 days and who were subsequently followed up 14–21 days after, in Salvador, Brazil. Data on recruitment were registered. The vaccine card was personally checked. Complication was defined when hospitalization, pneumonia or acute otitis media (AOM) were informed during the follow-up visit. Pneumonia and AOM were diagnosed by a doctor. Multiple logistic regression analysis was performed.ResultsOf 576 children, 422 (73%) returned and 79 (19%; 95%CI: 15–23%) had complications. The mean interval between admission and follow-up was 23 ± 13 days. Pneumonia (n = 47; 11%), hospitalization (n = 28; 7%), and AOM (n = 17; 4%) were reported. Most of the patients presented one complication (n = 66; 84%) followed by two (n = 13; 16%). Report of fever (92% versus 79%; OR [95%CI]: 2.90 [1.18–7.14]), bird at home (24% versus 14%; OR [95%CI]: 2.13 [1.07–4.26]), ronchi (48% versus 36%; OR [95%CI]: 2.06 [1.16–3.67]) or crackles (17% versus 7%; OR [95%CI]: 2.36 [1.04–5.38]) on auscultation were directly associated with complications whereas PCV10 (59% versus 75%; OR [95%CI]: 0.46 [0.26–0.82]) was inversely associated. Bird at home (OR [95%CI]: 5.80 [1.73–19.38]) and ronchi (OR [95%CI]: 6.39 [1.96–20.85]) were associated with AOM; PCV10 was inversely associated with AOM (OR [95%CI]: 0.16 [0.05–0.52]). Crackles were associated with pneumonia (OR [95%CI]: 2.55 [1.01–6.40]).ConclusionsOne fifth of the children presented complications. PCV10 was independently associated with lower odds of development of AOM. Bird at home and ronchi are risk factors of otitis. Crackles are associated with pneumonia.     

Impact of the 13-valent pneumococcal conjugate vaccine on Streptococcus pneumoniae multiple serotype carriage

IntroductionPneumococcal multiple serotype carriage is important for evolution of the species and to understand how the pneumococcal population is changing with vaccination. We aimed to determine the impact of the 13-valent pneumococcal conjugate vaccine (PCV13) on multiple serotype carriage.Methods and materialsNasopharyngeal samples from fully vaccinated pneumococcal carriers (4 doses of PCV13, n = 141, aged 18–72 months) or from non-vaccinated pneumococcal carriers (0 doses of any PCV, n = 140, same age group) were analyzed. Multiple serotype carriage was evaluated by DNA hybridization with a molecular serotyping microarray that detects all known serotypes.ResultsVaccinated children had a lower prevalence of multiple serotype carriage than the non-vaccinated group (20.6% vs 29.3%, p = 0.097), and a significantly lower proportion of PCV13 serotypes (6.4% vs 38.5%, p = 0.0001). PCV13 serotypes found among vaccinated children were mostly detected as a minor serotype in co-colonization with a more abundant non-vaccine serotype. Vaccinated children were colonized by a significantly higher proportion of commensal non-pneumococcal Streptococcus spp. (58.2% vs 42.8%, p = 0.012). In vaccinated children there were significantly less non-vaccine type (NVT) co-colonization events than expected based on the distribution of these serotypes in non-vaccinated children.ConclusionsThe results suggest that vaccinated children have lower pneumococcal multiple serotype carriage prevalence due to higher competitive abilities of non-vaccine serotypes expanding after PCV13 use. This might represent an additional benefit of PCV13, as decreased co-colonization rates translate into decreased opportunities for horizontal gene transfer and might have implications for the evolution and virulence of pneumococci.