Three-dose Primary Series Research Articles

The Battle against Diphtheria: Nigeria's Ongoing Struggle

Abstract:: Corynebacterium diphtheriae is a Gram-positive, rod-shaped, nonmotile bacillus. Lysogenic strains carry the diphtheria toxin gene (tox) on corynebacteriophages. It's categorized into biotypes and lysotypes based on colony morphology and phage sensitivity. The disease involves the upper respiratory tract, causing symptoms like fever and painful throat, with severe cases forming airway-blocking pseudomembranes [1-3]. Different types of diphtheria exist; incomplete immunization and poor healthcare facilities increase the risk. Diphtheria is treated with diphtheria antitoxin administered intravenously or intramuscularly, along with antibiotics. Timely treatment improves outcomes and reduces transmission. Lifetime immunity is achieved through a three-dose primary series during infancy and booster shots during childhood and adolescence [4]. : Since epidemiological week 26, concluding on July 2, 2023, Nigeria has witnessed a significant surge in diphtheria cases spanning multiple states. Between June 30 and August 31, 2023, 5,898 suspected cases were documented across 59 Local Government Areas (LGAs) in 11 states. In week 34, ending on August 27, 2023, 234 suspected cases were reported from 20 LGAs in five states, with one laboratory-confirmed case out of 22 samples collected. Among these cases, 18 were linked through epidemiological analysis, and 141 were categorized as clinically compatible [5]. Diphtheria incidence has decreased due to widespread DTaP vaccination in children, but declining childhood immunity necessitates booster shots. Recent outbreaks in some nations emphasize the need to maintain high vaccination rates. In Nigeria, a 2022 outbreak resulted in over 600 tragic deaths and around 14,000 suspected cases, a stark contrast to the 2011 outbreak with only 98 reported cases [6]. : In response to the ongoing diphtheria outbreak in Nigeria, the country has implemented several strategies and precautions to combat the disease. Here are the key measures being taken

Effectiveness of tick-borne encephalitis vaccination in Latvia, 2018–2020: an observational study

ObjectivesTick-borne encephalitis (TBE) is an infection by the tick-borne encephalitis virus (TBEV) that results in symptoms of central nervous system inflammation. TBE is endemic in Latvia and other European countries. TBE vaccines are commonly used in Latvia, but vaccine effectiveness estimates are limited. MethodsStudy staff at Rīga Stradinš University conducted nationwide active surveillance for TBEV infections. Serum and cerebrospinal fluid were ELISA-tested for TBEV-specific IgG and IgM antibodies. Vaccination history was collected by interview and medical record review. Utilizing data from surveillance and population surveys, vaccine effectiveness (with 95% CIs) and cases averted were estimated using the screening method. ResultsThere were 587 laboratory-identified TBE cases from 2018 to 2020; 98.1% (576/587) were unvaccinated, 1.5% (9/587) were unknown or partially vaccinated, and 0.3% (2/587) were fully vaccinated (three-dose primary series and appropriately timed boosters). TBE resulted in the death of 1.7% (10/587) of TBE cases. TBE vaccine history was ascertained from 92.0% (13 247/14 399) people from the general population: 38.6% (5113/13 247) were unvaccinated, 26.3% (3484/13 247) were fully vaccinated, and 35.1% (4650/13 247) were partially vaccinated. TBE vaccine effectiveness was 99.5% (98.0–99.9) against TBE, 99.5% (97.9–99.9) against TBE hospitalization, 99.3% (94.8–99.9) against moderate/severe TBE, and 99.2% (94.4–99.9) against TBE hospitalization >12 days. From 2018 to 2020, vaccination averted 906 TBE cases, including 20 deaths. DiscussionTBE vaccine was highly effective in preventing TBE, moderate and severe disease, and prolonged hospitalization. To prevent life-threatening TBE, TBE vaccine uptake and compliance should be increased in Latvia and other European regions where TBE is endemic.

Hepatitis B virus immunity prior to and after administration of a ‘booster’ dose of vaccine among health-care students at a South African university

BackgroundHealth-care students (HCSs) are at risk of occupational exposure to hepatitis B virus (HBV) infection despite an effective hepatitis B vaccine (HepB) being available. The majority of current HCSs are born after HepB was introduced into the South African Expanded Programme on Immunisation in 1995. Thus, it is assumed that having received HepB in infancy, a single ‘booster’ dose would suffice. This study aimed to investigate HBV immunity prior to and after administration of a HepB ‘booster’ dose. MethodsHepatitis B surface antibody (anti-HBs) levels were determined in first year HCSs at the University of the Witwatersrand, before and after receiving the ‘booster’. Participant demographics and HepB history were captured using a structured questionnaire. ResultsBefore receiving the ‘booster’, 56% (101/180) had anti-HBs < 10 mIU/mL and were non-immune. A further 35% had anti-HBs levels of 10 – 99 mIU/mL, and 9% had ≥100 mIU/mL. <30% of HCSs self-reported completion of a three-dose primary series, which was significantly associated with higher baseline anti-HBs levels compared to those with a partial schedule (p = 0.045). Following vaccination, 39% (71/180) returned for follow-up with a significant median (IQR) increase of 476 (151 – 966) mIU/mL (p < 0.001). Of the 45 students who had non-immune baseline levels, 73% (33/45) responded with ≥100 mIU/mL, 16% (7/45) with 10 – 99 mIU/mL and 11% (5/45) remained non-immune. Levels of ≥100 mIU/mL were achieved by 100% of students with baseline levels ≥10 mIU/mL (n = 26). ConclusionMore than half of the HCSs were not immune to HBV prior to receiving the recommended ‘booster’ vaccine. Following vaccination, 7% (5/71) remained unprotected. This study highlights that in the absence of vaccination records and without confirming the immune status of HCSs, it cannot be assumed that HCSs will be protected following a ‘booster’. Policy reform and inclusion of serological tests for immunity prior to HCSs initiating clinical exposure are recommended.

Recommendations for modernizing infant vaccination schedules with combination vaccines in Colombia and Peru.

The objective of this article was to consider the vaccination challenges in Colombia and Peru and the role of pediatric combination vaccines in overcoming these challenges. Barriers to including new vaccines with more antigens remain apparent in parts of these countries, where vaccine-preventable diseases in infants continue to be a major problem. The challenges include the heterogeneity of vaccine coverage within each country and in neighboring countries, which can contribute to poor rates of vaccination coverage; the adverse impact of the inward migration of unvaccinated individuals, which has favored the re-emergence of vaccine-preventable diseases; vaccine shortages; and the impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and the associated shifts in health care resources. To improve the coverage of pediatric vaccines in Colombia and Peru, it will be necessary to ensure the widespread integration into vaccine schedules of combination vaccines containing diphtheria, tetanus, acellular pertussis, inactivated poliovirus, Haemophilus influenzae type b and hepatitis B antigens with a three-dose primary series delivered at 2, 4 and 6 months of age followed by a booster at 18 months of age. Such vaccines play important roles in preventing diphtheria, tetanus and pertussis; eradicating polio; and providing boosting against H. influenzae type b.

Effect of different schedules of ten-valent pneumococcal conjugate vaccine on pneumococcal carriage in Vietnamese infants: results from a randomised controlled trial

WHO recommends a three-dose infant pneumococcal conjugate vaccine (PCV) schedule administered as a two-dose primary series with booster (2+1) or a three-dose primary series (3+0). Data on carriage impacts of these and further reduced PCV schedules are needed to inform PCV strategies. Here we evaluate the efficacy against carriage of four different PCV10 schedules. Participants within an open-label, randomised controlled trial in Ho Chi Minh City, Vietnam, were allocated to receive PCV10 in a 3+1 (2,3,4,9 months, n=152), 3+0 (2,3,4 months, n=149), 2+1 (2,4,9.5 months, n=250) or novel two-dose (2,6 months, n=202) schedule, or no infant doses of PCV (two control groups, n=197 and n=199). Nasopharyngeal swabs collected between 2 and 24 months were analysed (blinded) for pneumococcal carriage and serotypes. Trial registration: ClinicalTrials.gov NCT01953510. Pneumococcal carriage prevalence was low (10.6-14.1% for vaccine-type (VT) at 12-24 months in unvaccinated controls). All four PCV10 schedules reduced VT carriage compared with controls (the 2+1 schedule at 12, 18, and 24 months; the 3+1 and two-dose schedules at 18 months; and the 3+0 schedule at 24 months), with maximum reductions of 40.1%-64.5%. There were no differences in VT carriage prevalence at 6 or 9 months comparing three-dose and two-dose primary series, and no differences at 12, 18, or 24 months when comparing schedules with and without a booster dose. In Vietnamese children with a relatively low pneumococcal carriage prevalence, 3+1, 2+1, 3+0 and two-dose PCV10 schedules were effective in reducing VT carriage. There were no discernible differences in the effect on carriage of the WHO-recommended 2+1 and 3+0 schedules during the first two years of life. Together with the previously reported immunogenicity data, this trial suggests that a range of PCV schedules are likely to generate significant direct and indirect protection. NHMRC, BMGF.

Immunogenicity of a Three-Dose Primary Series of mRNA COVID-19 Vaccines in Patients With Lymphoid Malignancies.

BackgroundPatients with lymphoid malignancies are at risk for poor coronavirus disease 2019 (COVID-19)-related outcomes and have reduced vaccine-induced immune responses. Currently, a 3-dose primary regimen of mRNA vaccines is recommended in the United States for immunocompromised hosts.MethodsA prospective cohort study of healthy adults (n = 27) and patients with lymphoid malignancies (n = 94) was conducted, with longitudinal follow-up through completion of a 2- or 3-dose primary mRNA COVID vaccine series, respectively. Humoral responses were assessed in all participants, and cellular immunity was assessed in a subset of participants.ResultsThe rate of seroconversion (68.1% vs 100%) and the magnitude of peak anti-S immunoglobulin G (IgG) titer (median anti-S IgG = 32.4, IQR = 0.48–75.0 vs median anti-S IgG = 72.6, IQR 51.1–100.1; P = .0202) were both significantly lower in patients with lymphoid malignancies compared to the healthy cohort. However, peak titers of patients with lymphoid malignancies who responded to vaccination were similar to healthy cohort titers (median anti-S IgG = 64.3; IQR, 23.7–161.5; P = .7424). The third dose seroconverted 7 of 41 (17.1%) patients who were seronegative after the first 2 doses. Although most patients with lymphoid malignancies produced vaccine-induced T-cell responses in the subset studied, B-cell frequencies were low with minimal memory cell formation.ConclusionsA 3-dose primary mRNA series enhanced anti-S IgG responses to titers equivalent to healthy adults in patients with lymphoid malignancies who were seropositive after the first 2 doses and seroconverted 17.1% who were seronegative after the first 2 doses. T-cell responses were present, raising the possibility that the vaccines may confer some cell-based protection even if not measurable by anti-S IgG.

Post-Marketing Surveillance of Tetravalent Diphtheria-Tetanus-Acellular Pertussis and Inactivated Poliovirus (DTaP-IPV) Vaccine in South Korea, 2009 to 2015.

IntroductionTETRAXIM™ (Sanofi), a combined diphtheria, tetanus, acellular pertussis, and inactivated poliovirus (DTaP-IPV) vaccine, has been licensed in South Korea since 2009. In accordance with the Ministry of Food and Drug Safety regulations, this post-marketing surveillance (PMS) study evaluated the safety of the DTaP-IPV vaccine in real-world clinical practice in infants and children who received it as either a part of the three-dose primary series dose at 2, 4, and 6 months or school entry booster between 4 and 6 years of age.MethodsThis multicenter, observational, PMS study was conducted in real-world practice in South Korea for 6 years (2009–2015) in participants aged between 2 months and 6 years. The study outcomes included solicited reactions, unsolicited adverse events (AEs)/adverse drug reactions (ADRs), unexpected AEs/ADRs, and serious AEs (SAEs)/ADRs.ResultsData from 647 participants was included in the safety analysis. Overall, 268 AEs were reported by 181 (28%) participants: 47 (17.5%) solicited reactions, 220 (82.1%) unsolicited AEs, and 1 (0.4%) unsolicited ADR. A total of 48 AEs (including 47 solicited reactions) were reported to have a causal relationship with the DTaP-IPV vaccine and were reported by 36 (5.6%) participants. A total of 212 unexpected AEs were reported by 152 (23.5%) participants, none of which had a causal relationship with the DTaP-IPV vaccine. Neither immediate AEs nor SAEs were reported during the study. Among the participants who reported AEs, 220 (34%) were on concomitant medications. Most AEs were of mild intensity, and all participants recovered.ConclusionNo safety concerns related to the DTaP-IPV vaccine in a real-world setting were raised in participants aged 2–6 months for the primary series and 4–6 years for the school-entry booster dose in the Korean population. The DTaP-IPV vaccine was well tolerated and can be continued as part of routine immunization programs in infants and children.Trial Registration: NCT01437423.

Three-dose versus four-dose primary schedules for tick-borne encephalitis (TBE) vaccine FSME-immun for those aged 50 years or older: A single-centre, open-label, randomized controlled trial

BackgroundTBE vaccination failures among those past middle age have raised concern about immune response declining with age. We investigated immunogenicity of the TBE-vaccine FSME-Immun among those aged 50+ years using the standard three-dose primary series and alternative four-dose schedules. MethodsIn this single-centre, open-label, randomized controlled trial, 200 TBE-naive Swedish adults were given primary TBE vaccination with FSME-Immun. Those aged 50+ years (n = 150) were randomized to receive the standard three-dose (days 0–30–360) or one of two four-dose series (0–7–21–360; 0–30–90–360). For participants < 50 years (n = 50) the standard three-dose schedule was used. Titres of neutralizing antibodies were determined on days 0, 60, 120, 360, and 400. The main outcome was the log titre of TBE virus-specific neutralizing antibodies on day 400. ResultsThe three-dose schedule yielded lower antibody titres among those aged 50+ years than the younger participants on day 400 (geometric mean titre 41 versus 74, p < 0.05). The older group showed higher titres for the four-dose 0–7–21–360 than the standard three-dose schedule both on day 400 (103 versus 41, p < 0.01; primary end point) and at the other testing points (days 60, 120, 360). Using the other four-dose schedule (0–30–90–360), no such difference was observed on day 400 (63 versus 41, NS). ConclusionImmune response to the TBE vaccine declined with age. A four-dose schedule (0–7–21–360) may benefit those aged 50 years or older. This study is registered at ClinicalTrials.gov, NCT01361776.

Estimating the economic burden of pneumococcal meningitis and pneumonia in northern Ghana in the African meningitis belt post-PCV13 introduction

BackgroundGhana introduced 13-valent pneumococcal conjugate vaccine (PCV13) into the routine infant immunization program in 2012, using a three-dose primary series without a booster. Despite ≥ 88% reported three-dose vaccination coverage since 2013, PCV13-type pneumococcal meningitis outbreaks have occurred. We estimated the ongoing economic burden of PCV13-type pneumococcal meningitis and pneumonia in northern Ghana, an area within the African meningitis belt with seasonal increases of pneumococcal meningitis post-PCV13 introduction, to inform PCV13 vaccination policy. MethodsWe performed a cross-sectional survey among patients with pneumonia or meningitis at three hospitals in northern Ghana to determine patient-level costs (direct medical and nonmedical, indirect patient and caregiver costs) incurred in household, outpatient, and inpatient settings. Pneumonia burden was estimated using 2017–2018 administrative records. Pneumococcal meningitis burden was estimated using 2017–2018 case-based surveillance data. Economic burden was reported in 2019 U.S. dollars ($) from the societal perspective. ResultsFor an area with a total population of 5,068,521, our model estimated 6,441 PCV13-type pneumonia cases and 286 PCV13-type meningitis cases occurred in a typical year post-PCV13. In the base case scenario, the total economic burden was $5,230,035 per year ($777 per case). By age group, cost per PCV13-type pneumonia case was $423 (<5 years), $911 (5–14 years), and $784 (≥15 years); cost per PCV13-type meningitis case was $2,128 (<5 years), $3,247 (5–14 years), and $2,883 (≥15 years). Most (78.0–93.4%) of the total societal cost was due to indirect costs related to deaths from PCV13-type diseases. ConclusionsThe estimated economic burden of PCV13-type disease in northern Ghana remains substantial, especially in older children and adults who were expected to have benefited from indirect effects from infant immunization. Additional interventions such as changes in the infant immunization schedule, reactive vaccination, or catch-up PCV13 vaccination may be needed to control remaining vaccine-type disease.

Immunogenicity of alternative ten-valent pneumococcal conjugate vaccine schedules in infants in Ho Chi Minh City, Vietnam: results from a single-blind, parallel-group, open-label, randomised, controlled trial

SummaryBackgroundData are scarce from low-income and middle-income countries (LMICs) to support the choice of vaccination schedule for the introduction of pneumococcal conjugate vaccines (PCV). We aimed to compare the immunogenicity of four different infant PCV10 schedules in infants in Vietnam.MethodsIn this single-blind, parallel-group, open-label, randomised controlled trial, infants aged 2 months were recruited by community health staff in districts 4 and 7 of Ho Chi Minh City, Vietnam. Eligible infants had no clinically significant maternal or prenatal history and were born at or after 36 weeks' gestation. Participants were randomly assigned (3:3:5:4:5:4) using block randomisation, stratified by district, to one of six PCV10 or PCV13 vaccination schedules. Here we report results for four groups: group A, who were given PCV10 at ages 2, 3, 4, and 9 months (a 3 + 1 schedule); group B, who were vaccinated at ages 2, 3, and 4 months (3 + 0 schedule); group C, who were vaccinated at ages 2, 4, and 9·5 months (2 + 1 schedule); and group D, who were vaccinated at ages 2 and 6 months (two-dose schedule). Laboratory-based assessors were masked to group allocation. Blood samples were collected at different prespecified timepoints between ages 3–18 months depending on group allocation, within 27–43 days after vaccination, and these were analysed for serotype-specific IgG and opsonophagocytic responses. Participants were followed-up until age 24 months. The primary outcome was the proportion of infants with serotype-specific IgG levels of 0·35 μg/mL or higher at age 5 months, analysed as a non-inferiority comparison (10% margin) of the two-dose and three-dose primary series (group C vs groups A and B combined). We also compared responses 4 weeks after two doses administered at either ages 2 and 4 months (group C) or at ages 2 and 6 months (group D). The primary endpoint was analysed in the per-protocol population. Reactogenicity has been reported previously. This study is registered with ClinicalTrials.gov, NCT01953510, and is now closed to accrual.FindingsBetween Sept 30, 2013, and Jan 9, 2015, 1201 infants were enrolled and randomly assigned to group A (n=152), group B (n=149), group C (n=250), group D (n=202), or groups E (n=251) and F (n=197). In groups A–D, 388 (52%) of 753 participants were female and 365 (48%) were male. 286 (95%) participants in groups A and B combined (three-dose primary series) and 237 (95%) in group C (two-dose primary series) completed the primary vaccination series and had blood samples taken within the specified time window at age 5 months (per-protocol population). At this timepoint, a two-dose primary series was non-inferior to a three-dose primary series for eight of ten vaccine serotypes; exceptions were 6B (84·6% [95% CI 79·9–88·6] of infants had protective IgG concentrations after three doses [groups A and B combined] vs 76·8% [70·9–82·0] of infants after two doses [group C]; risk difference 7·8% [90% CI 2·1–13·6]) and 23F (90·6% [95% CI 86·6–93·7] vs 77·6% [71·8–82·2]; 12·9% [90% CI 7·7–18·3]). Two doses at ages 2 and 6 months produced higher antibody levels than two doses at ages 2 and 4 months for all serotypes except 5 and 7F.InterpretationA two-dose primary vaccination series was non-inferior to a three-dose primary vaccination series while two doses given with a wider interval between doses increased immunogenicity. The use of a two-dose primary vaccination schedule using a wider interval could be considered in LMIC settings to extend protection in the second year of life.FundingAustralian National Health and Medical Research Council, and The Bill & Melinda Gates Foundation.

Implementation and adherence of routine pertussis vaccination (DTP) in a low-resource urban birth cohort

IntroductionReliable information on rates of up-to-date coverage and timely administration of routine childhood immunisations are critical for guiding public health efforts worldwide, yet prospective observation of vaccination programmes within individual...

Effect of HIV-exposure and timing of antiretroviral treatment initiation in children living with HIV on antibody persistence and memory responses to Haemophilus influenzae type b and pneumococcal polysaccharide-protein conjugate vaccines

BackgroundWe investigated the effect of in utero HIV-exposure, timing of antiretroviral treatment (ART) initiation, and ART interruption on memory responses and persistence of immunity induced by pneumococcal (PCV) and Haemophilus influenzae type b (HibCV) polysaccharide-protein conjugate vaccines. MethodsChildren were enrolled (6–12 weeks of age), and vaccinated with a three-dose primary series of 7-valent PCV (PCV7) and HibCV at 6, 10 and 14 weeks of age. Study groups included infants infected with HIV perinatally with CD4+ ≥ 25% initiating ART following immunological or clinical deterioration (ART-Def), or immediately upon enrolment followed by interruption at 40 (ART-Immed/40w) or 96 weeks (ART-Immed/96w); and HIV-uninfected infants with (HEU), and without HIV (HIV-unexpsoed) exposure in utero. Within each group, children were randomized to receive either a booster dose of PCV7 or HibCV at 15 months of age. PCV serotype-specific and polyribosyl ribitol phosphate (PRP) IgG were measured pre-boost, two-weeks post-boost and at two-years of age. Opsonophagocytic activity (OPA) to serotypes 9V, 19F and 23F was measured post-booster dose. ResultsPersistence of IgG to PCV vaccine–serotypes and anti-PRP was similar in all groups of children living with HIV (CLWH) compared to HIV-unexposed children. Anamnestic responses to PCV and HibCV were also similar in all three groups of CLWH compared to HIV-unexposed children. CLWH, however, tended to have lower functional antibody (OPA) titers than HIV-unexposed children after the PCV booster dose for some serotypes. Immunity to PCV and HibCV was similar between the ART-Immed/40w and ART-Immed-96w groups. There were no differences in IgG kinetics between HEU and HIV-unexposed children. ConclusionsA three dose primary series, with or without PCV or HibCV booster doses in CLWH initiated on ART during infancy, would likely be similarly effective in preventing invasive bacterial disease as in HIV-unexposed children.

The duopoly of ten-valent and 13-valent pneumococcal conjugate vaccines: do they differ?

The duopoly of ten-valent and 13-valent pneumococcal conjugate vaccines: do they differ?

Immunogenicity and reactogenicity of ten-valent versus 13-valent pneumococcal conjugate vaccines among infants in Ho Chi Minh City, Vietnam: a randomised controlled trial

SummaryBackgroundFew data are available to support the choice between the two currently available pneumococcal conjugate vaccines (PCVs), ten-valent PCV (PCV10) and 13-valent PCV (PCV13). Here we report a head-to-head comparison of the immunogenicity and reactogenicity of PCV10 and PCV13.MethodsIn this parallel, open-label, randomised controlled trial, healthy infants from two districts in Ho Chi Minh City, Vietnam, were randomly allocated (in a 3:3:5:4:5:4 ratio), with use of a computer-generated list, to one of six infant PCV schedules: PCV10 in a 3 + 1 (group A), 3 + 0 (group B), 2 + 1 (group C), or two-dose schedule (group D); PCV13 in a 2 + 1 schedule (group E); or no infant PCV (control; group F). Blood samples were collected from infants between 2 months and 18 months of age at various timepoints before and after PCV doses and analysed (in a blinded manner) by ELISA and opsonophagocytic assay. The trial had two independent aims: to compare vaccination responses between PCV10 and PCV13, and to evaluate different schedules of PCV10. In this Article, we present results pertaining to the first aim. The primary outcome was the proportion of infants with an IgG concentration of at least 0·35 μg/mL for the ten serotypes common to the two vaccines at age 5 months, 4 weeks after the two-dose primary vaccination series (group C vs group E, per protocol population). An overall difference among the schedules was defined as at least seven of ten serotypes differing in the same direction at the 10% level. We also assessed whether the two-dose primary series of PCV13 (group E) was non-inferior at the 10% level to a three-dose primary series of PCV10 (groups A and B). This trial is registered with ClinicalTrials.gov, number NCT01953510.FindingsOf 1424 infants screened between Sept 30, 2013, and Jan 9, 2015, 1201 were allocated to the six groups: 152 (13%) to group A, 149 (12%) to group B, 250 (21%) to group C, 202 (17%) to group D, 251 (21%) to group E, and 197 (16%) to group F. 237 (95%) participants in group C (PCV10) and 232 (92%) in group E (PCV13) completed the primary vaccination series and had blood draws within the specified window at age 5 months, at which time the proportion of infants with IgG concentrations of at least 0·35 μg/mL did not differ between groups at the 10% level for any serotype (PCV10–PCV13 risk difference −2·1% [95% CI −4·8 to −0·1] for serotype 1; −1·3% [–3·7 to 0·6] for serotype 4; −3·4% [–6·8 to −0·4] for serotype 5; 15·6 [7·2 to 23·7] for serotype 6B; −1·3% [–3·7 to 0·6] for serotype 7F; −1·6% [–5·1 to 1·7] for serotype 9V; 0·0% [–2·7 to 2·9] for serotype 14; −2·1% [–5·3 to 0·9] for serotype 18C; 0·0% [–2·2 to 2·3] for serotype 19F; and −11·6% [–18·2 to −4·9] for serotype 23F). At the same timepoint, two doses of PCV13 were non-inferior to three doses of PCV10 for nine of the ten shared serotypes (excluding 6B). Reactogenicity and serious adverse events were monitored according to good clinical practice guidelines, and the profiles were similar in the two groups.InterpretationPCV10 and PCV13 are similarly highly immunogenic when used in 2 + 1 schedule. The choice of vaccine might be influenced by factors such as the comparative magnitude of the antibody responses, price, and the relative importance of different serotypes in different settings.FundingNational Health and Medical Research Council of Australia, and Bill & Melinda Gates Foundation.

Persistence and 4-year boosting of the bactericidal response elicited by two- and three-dose schedules of MenB-FHbp: A phase 3 extension study in adolescents

Persistence and 4-year boosting of the bactericidal response elicited by two- and three-dose schedules of MenB-FHbp: A phase 3 extension study in adolescents

Regional variations in serotype distribution and vaccination status in children under six years of age with invasive pneumococcal disease in Germany.

OverviewThe protective effect of infant pneumococcal conjugate vaccine (PCV) recommendation can be seen in Germany as a whole and in smaller regional groups. Comparisons between population-normalized geographic regions of Germany show different serotype distributions after program implementation, particularly in non-vaccine serotypes. The prior distinct differences in serotype distribution in children between the former East and former West German federal states have vanished. Children under six remain a vulnerable group, but the occurrence of vaccine-type (VT) invasive pneumococcal disease (IPD) in children correctly vaccinated (using a three-dose primary series plus one booster dose) with PCV13 was low (9 out of 374 cases, 2.4%). However, only 18.4% of children in Germany with IPD were correctly vaccinated with PCV13 according to the recommended schedule. Continued surveillance and better schedule adherence are essential to definitively establish the most effective PCV administration schedule.Vaccination effectsFor all PCV products used in Germany (PCV7, PCV10, and PCV13), vaccination status was the most common statistically significant predictor of infection with a particular serotype: Unvaccinated children old enough to have received at least one dose of vaccine in the PCV7 group had significantly higher odds (OR: 6.84, 95%CI: 2.66–22.06, adjusted for per capita income and residence in the northeastern federal states) of contracting VT IPD. In the PCV10 group, VT IPD had an OR of 4.52 (95% CI: 1.60–15.62, adjusted for year of infection, median household size, and residence in the southern federal states) in unvaccinated children, and in the PCV13 group, unvaccinated children continued to have higher odds (OR: 6.21, 95%CI: 3.45–11.36, adjusted for year of infection, age of child, per capita income, residence in the southern federal states, and percentage of children using public daycare) of getting vaccine-type IPD. Being unvaccinated was the most frequent significant indicator for infection with vaccine-type serotypes for each analysis group, while geographic groupings showed more limited potential to predict serotype of infection in early childhood IPD in Germany.

Safety, tolerability and immunogenicity of intramuscular administration of PRP-CRM197 Hib vaccine to healthy Japanese children: An open-label trial

BackgroundJapan licensed the conjugate Haemophilus influenzae type b vaccine, Vaxem™ Hib, based on clinical studies using subcutaneous injection. The present study was performed to ensure this vaccine is suitable for intramuscular injection in Japanese children. MethodsThirty-one healthy 2–6-month-old infants received three doses of Vaxem™ Hib by intramuscular injection at 4-week intervals and a booster dose 1 year later, concomitant with routine infant (DTaP-IPV and pneumococcal) and toddler (measles–rubella) vaccines. Immunogenicity was assessed before and after the primary series and booster dose by enzyme-linked immunosorbent assay for anti-polyribosyl-ribitol-phosphate (PRP) antibodies. Safety was assessed by medical examination and diary cards completed by the subjects’ parents/legal guardians. ResultsThere were no vaccine-related serious adverse events or withdrawals; all children completed the study. Four weeks after the primary series, the geometric mean anti-PRP titer (GMT) was 19.68 μg/mL, and all children had seroprotective titers (≥0.15 μg/mL) that persisted until the booster dose. Proportions of titers indicative of long-term protection (≥1.0 μg/mL) were 100% after the primary series and 77.4% before the booster. Anamnestic responses to the booster had a GMT of 51.33 μg/mL, and 100% had titers ≥1.0 μg/mL. All but one subject reported injection site reactions as resolved within 3 days of vaccination; systemic reactions due to Hib and routine vaccines were also resolved within this period. ConclusionsVaxem™ Hib was generally well tolerated and immunogenic in Japanese children when administered by intramuscular injection in a three-dose primary series and as a booster with concomitant routine vaccines.Clinical trial registry: Registered on Clinical Trials.gov: NCT02074345.

Comparison of serum bactericidal and antibody titers induced by two Haemophilus influenzae type b conjugate vaccines: A phase III randomized double-blind study

Haemophilus influenzae type b (Hib) conjugate vaccines have drastically reduced disease incidence worldwide. Protection against Hib infection has relied on the serum bactericidal activity (SBA) of antibodies to the Hib capsular polysaccharide (polyribosylribitol phosphate). However, licensure usually relies on measuring induction of antibodies to PRP as a surrogate for SBA. In a phase III clinical trial we compared a PRP-conjugate vaccine using the nontoxic diphtheria toxin mutant, CRM197, as carrier protein with the licensed tetanus toxoid conjugate when administered subcutaneously as a three dose primary series in Japanese infants. As an addition to the phase III study, we have now evaluated SBA and show PRP-CRM197 induces higher levels of SBA than PRP-T four weeks after the primary series, with a statistically significant correlation with anti-PRP titers. This data confirms the superior immunogenicity of PRP-CRM197 compared with PRP-T assessed as SBA following a three-dose primary series by subcutaneous administration.Clinical trial registry: Registered on ClinicalTrials.gov (NCT01379846).

Haemophilus Influenzae Type B Invasive Disease in a Pediatric Hospital of Argentina

BackgroundSinceThe vaccination strategy is a three-dose primary series (at two,Active surveillance is important to opportunely detect variations on these trends.MethodsCross-sectional study, including all hospitalized patients with Hib infection since 2012 to May 2017 at Hospital de Niños “Ricardo Gutiérrez” in Buenos Aires, Argentina.ResultsTwenty previously healthy children were admitted. Male/female ratio 1.8:1. Median age: 12 (range 45 days-114) months; 85% younger than 2 years and 35% younger than 6 months. Nine patients (45%) had complete vaccination schedule, with three or more doses of DTP-Hib-HBV vaccine. Hospitalization Hib infections by year in Table 1.YearHib admissions (n)Total hospital admissions (n)Hospitalization rates (per 100.000 admissions/year)201219,7641,02201329,3042,15(IC 95% 0.26–7.76)201439,0663,31(IC95% 0.68–13.81)201569,4506,35 (IC 95% 2.33–13.81)201689,7808,18 (IC 95% 3.5– 6.11)Clinical presentation: meningitis (14/20), pneumonia (6/20) and arthritis (5/20), osteomyelitis (1/20). All patients with meningitis, 25% of pneumonias and 50% of arthritis had positive blood cultures. Hib was isolated from blood in 17/20 cases, cerebrospinal fluid in 7/14, joint fluid in 3/5 and pleural fluid in 2/6. Median WBC: 12,400/mm3 (1,600–42,900) and median C-reactive protein level 111 mg/L (7–358). Median days of hospitalization was 13 (8–40). Nine patients required intensive care, four of them required mechanical ventilation. None patients died. Immunological studies ruled out immunodeficiency in 10 patients, although four continues under study.Conclusion(i) Burden of invasive Hib infections have increased over the last few years in our setting. (ii) Most of patient had adequate immunization schedule for age; (iii) Surveillance studies should be continued to confirm these preliminary results as well as to evaluate possible causes.Disclosures All authors: No reported disclosures.

Antibody persistence and evidence of immune memory at 5years following administration of the 9-valent HPV vaccine.

The 9-valent HPV (9vHPV) vaccine was developed to prevent infection and disease related to 9 HPV types (HPV6/11/16/18/31/33/45/52/58) which cause approximately 90% of cervical cancers, HPV-related vulvar, vaginal and anal cancers, and genital warts worldwide. In a pivotal efficacy study, the 9vHPV vaccine prevented infection and disease due to the 9 vaccine types. Duration of protection remains to be determined. Vaccines that induce long-term protection are generally characterized by the generation of immune memory. The purpose of this report is to assess the persistence of HPV antibody response and existence of immune memory at 5years post-vaccination. A subset of subjects (N=150) who received 3 doses of 9vHPV vaccine at day 1, month 2 and month 6 in the pivotal efficacy study continued in a study extension and received a fourth dose of 9vHPV vaccine at month 60. Serum HPV antibody levels were measured pre-dose 4 and at 7 and 28days post-dose 4 by competitive Luminex immunoassay. Adverse events were assessed using a vaccination report card. HPV antibodies induced following the 3-dose series of 9vHPV vaccine in the base study persisted through month 60 with seropositivity rates ranging from 77.5% to 100%. Geometric mean titers at 1week and 1month post-dose 4 were 1.25-4.10 and 1.65-4.88-fold higher, respectively, than levels observed 1month following the completion of the three-dose primary series. Seropositivity rates were >99% and 100% at 1week and 1month post-dose 4, respectively. The fourth dose of 9vHPV vaccine was generally well tolerated. A three-dose regimen of the 9vHPV vaccine induced persistent HPV antibody response through 5years post-vaccination. Administration of a fourth dose resulted in a strong anamnestic response to all 9 vaccine types. These findings suggest that the efficacy of the 9vHPV vaccine will be long lasting. Clinical Trials.gov Identifier:NCT00543543.