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The relationship between pneumococcal conjugate vaccine-induced antibody responses and protection against community-acquired pneumonia (CAP) and acute otitis media (AOM) is unclear. This study assessed the impact of the ten-valent pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on these end points. The primary objective was to demonstrate vaccine efficacy (VE) in a per-protocol analysis against likely bacterial CAP (B-CAP: radiologically confirmed CAP with alveolar consolidation/pleural effusion on chest X-ray, or non-alveolar infiltrates and C-reactive protein ≥ 40 µg/ml); other protocol-specified outcomes were also assessed. This phase III double-blind randomized controlled study was conducted between 28 June 2007 and 28 July 2011 in Argentine, Panamanian, and Colombian populations with good access to health care. Approximately 24,000 infants received PHiD-CV or hepatitis control vaccine (hepatitis B for primary vaccination, hepatitis A at booster) at 2, 4, 6, and 15-18 mo of age. Interim analysis of the primary end point was planned when 535 first B-CAP episodes, occurring ≥2 wk after dose 3, were identified in the per-protocol cohort. After a mean follow-up of 23 mo (PHiD-CV, n = 10,295; control, n = 10,201), per-protocol VE was 22.0% (95% CI: 7.7, 34.2; one-sided p = 0.002) against B-CAP (conclusive for primary objective) and 25.7% (95% CI: 8.4%, 39.6%) against World Health Organization-defined consolidated CAP. Intent-to-treat VE was 18.2% (95% CI: 5.5%, 29.1%) against B-CAP and 23.4% (95% CI: 8.8%, 35.7%) against consolidated CAP. End-of-study per-protocol analyses were performed after a mean follow-up of 28-30 mo for CAP and invasive pneumococcal disease (IPD) (PHiD-CV, n = 10,211; control, n = 10,140) and AOM (n = 3,010 and 2,979, respectively). Per-protocol VE was 16.1% (95% CI: -1.1%, 30.4%; one-sided p = 0.032) against clinically confirmed AOM, 67.1% (95% CI: 17.0%, 86.9%) against vaccine serotype clinically confirmed AOM, 100% (95% CI: 74.3%, 100%) against vaccine serotype IPD, and 65.0% (95% CI: 11.1%, 86.2%) against any IPD. Results were consistent between intent-to-treat and per-protocol analyses. Serious adverse events were reported for 21.5% (95% CI: 20.7%, 22.2%) and 22.6% (95% CI: 21.9%, 23.4%) of PHiD-CV and control recipients, respectively. There were 19 deaths (n = 11,798; 0.16%) in the PHiD-CV group and 26 deaths (n = 11,799; 0.22%) in the control group. A significant study limitation was the lower than expected number of captured AOM cases. Efficacy was demonstrated against a broad range of pneumococcal diseases commonly encountered in young children in clinical practice. www.ClinicalTrials.gov NCT00466947.

Rising Lyme borreliosis incidence rates, potential for severe outcomes, and limitations in accurate and timely diagnosis for treatment initiation suggest the need for a preventive vaccine; however, no vaccine is currently available for human use. We performed two studies in adults to optimise the dose level and vaccination schedule for VLA15, an investigational Lyme borreliosis vaccine targeting outer surface protein A (OspA) serotypes 1–6, which are associated with the most common pathogenic Borrelia species in Europe and North America. Both randomised, observer-blind, placebo-controlled, multicentre phase 2 studies included participants aged 18–65 years without recent history of Lyme borreliosis or tick bites. Study one was conducted at nine clinical research and study centre sites in the USA (n=6), Germany (n=2), and Belgium (n=1); study two was conducted at five of the study one US sites. Based on a randomisation list created by an unmasked statistician for each study, participants were randomly assigned via an electronic case report form randomisation module to receive 90 μg (study one only), 135 μg, or 180 μg VLA15 or placebo by intramuscular injection at months 0, 1, and 2 (study one) or 0, 2, and 6 (study two). Study one began with a run-in phase to confirm safety, after which the Data Safety Monitoring Board recommended the removal of the 90 μg group and continuation of the study. In the study one run-in phase, randomisation was stratified by study site, whereas in the study one main phase and in study two, randomisation was stratified by study site, age group, and baseline B burgdorferi (sensu lato) serostatus. All individuals were masked, other than staff involved in randomisation, vaccine preparation or administration, or safety data monitoring. The primary endpoint for both studies was OspA-specific IgG geometric mean titres (GMTs) at 1 month after the third vaccination and was evaluated in the per-protocol population. Safety endpoints were evaluated in the safety population: all participants who received at least one vaccination. Both studies are registered at ClinicalTrials.gov (study one NCT03769194 and study two NCT03970733) and are completed. For study one, 573 participants were screened and randomly assigned to treatment groups between Dec 21, 2018, and Sept, 26, 2019. For study two, 248 participants were screened and randomly assigned between June 26 and Sept 3, 2019. In study one, 29 participants were assigned to receive 90 μg VLA15, 215 to 135 μg, 205 to 180 μg, and 124 to placebo. In study two, 97 participants were assigned to receive 135 μg VLA15, 100 to 180 μg, and 51 to placebo. At 1 month after the third vaccination (ie, month 3), OspA-specific IgG GMTs in study one ranged from 74·3 (serotype 1; 95% CI 46·4–119·0) to 267·4 units per mL (serotype 3; 194·8–367·1) for 90 μg VLA15, 101·9 (serotype 1; 87·1–119·4) to 283·2 units per mL (serotype 3; 248·2–323·1) for 135 μg, and 115·8 (serotype 1; 98·8–135·7) to 308·6 units per mL (serotype 3; 266·8–356·8) for 180 μg. In study two, ranges at 1 month after the third vaccination (ie, month 7) were 278·5 (serotype 1; 214·9–361·0) to 545·2 units per mL (serotype 2; 431·8–688·4) for 135 μg VLA15 and 274·7 (serotype 1; 209·4–360·4) to 596·8 units per mL (serotype 3; 471·9–754·8) for 180 μg. Relative to placebo, the VLA15 groups had more frequent reports of solicited local adverse events (study one: 94%, 95% CI 91–96 vs 26%, 19–34; study two: 96%, 93–98 vs 35%, 24–49 after any vaccination) and solicited systemic adverse events (study one: 69%, 65–73 vs 43%, 34–52; study two: 74%, 67–80 vs 51%, 38–64); most were mild or moderate. In study one, unsolicited adverse events were reported by 52% (48–57) of participants in the VLA15 groups and 52% (43–60) of those in the placebo groups; for study two these were 65% (58–71) and 69% (55–80), respectively. Percentages of participants reporting serious unsolicited adverse events (study one: 2%, 1–4; study two: 4%, 2–7) and adverse events of special interest (study one: 1%, 0–2; study two: 1%, 0–3) were low across all groups. A single severe, possibly related unsolicited adverse event was reported (worsening of pre-existing ventricular extrasystoles, which resolved after change of relevant concomitant medication); no related serious adverse events or deaths were reported. VLA15 was safe, well tolerated, and elicited robust antibody responses to all six OspA serotypes. These findings support further clinical development of VLA15 using the 180 μg dose and 0-2-6-month schedule, which was associated with the greatest immune responses. Valneva.

Increasing incidence rates, insufficient effectiveness of exposure prevention strategies, and the potential for serious outcomes despite antibiotic treatment highlight the need for a preventive vaccine against Lyme borreliosis. VLA15, an investigational Lyme borreliosis vaccine based on outer surface protein A (OspA) variants from clinically relevant Borrelia burgdorferi sensu lato genospecies in North America and Europe, has shown safety and immunogenicity in adults when administered with various three-dose schedules. We aimed to investigate the safety and immunogenicity of two-dose and three-dose schedules of VLA15 within a broader population, including children and adolescents, who are among those at increased risk of Lyme borreliosis. This randomised, observer-blind, placebo-controlled phase 2 trial is taking place at 14 clinical study centres in Lyme borreliosis-endemic areas in the USA. Healthy, eligible participants aged 5–65 years were enrolled in a 2:1:1 ratio to age cohorts of 18–65 years, 12–17 years, and 5–11 years through a staggered age-descending enrolment process. Within each age cohort, participants were randomly assigned with an electronic data capture system in a 1:1:1 ratio to receive intramuscular injections of 180 μg VLA15 at months 0, 2, and 6 (VLA15 M0-2-6 group); 180 μg VLA15 at months 0 and 6, and placebo at month 2 (VLA15 M0-6 group); or placebo at months 0, 2, and 6. Unmasked individuals included site staff and clinical research associates involved in randomisation and handling the investigational product, as well as specific individuals, both internal and external to the sponsor, who regularly reviewed trial safety data (including statisticians preparing relevant tables). All other individuals were masked; unmasking after the database snapshot for month 7 analyses for each age cohort was limited to the trial sponsor, collaboration partner, and statisticians. The primary immunogenicity endpoint was OspA serotype (ST)-specific IgG geometric mean titres (GMTs) assessed by ELISAs at month 7 (ie, 1 month after the third vaccination) and was evaluated in the per-protocol analysis set. The primary safety endpoint was the frequency of solicited local and systemic adverse events occurring within 7 days after each and any vaccination and were assessed in the safety analysis set (ie, all individuals who received at least one vaccination). This report includes safety and immunogenicity data through to month 12. This trial is ongoing but no longer recruiting participants, and is registered with Clinicaltrials.gov (NCT04801420). Between March 15, 2021, and Feb 24, 2022, 625 participants (321 [51%] female, 304 [49%] male) received one or more vaccinations and were included in the safety analysis set. Of these, 190 participants were included in the VLA15 M0-2-6 group, 187 were included in the VLA15 M0-6 group, and 208 were included in the placebo group; 40 additional VLA15 recipients could not be allocated to either VLA15 group because their vaccination schedules were non-compliant with both VLA15 groups due to missed or incorrect vaccinations; however, these individuals were included in safety analyses. OspA-specific ELISA IgG GMTs at month 7 in the overall population (aged 5–65 years) were significantly higher in the VLA15 M0-2-6 group (333·2 [95% CI 275·2–403·4; ST1] to 656·0 [560·2–768·2; ST2] units per mL) and VLA15 M0-6 group (197·3 [156·2–249·3; ST1] to 460·3 [370·6–571·8; ST2] units per mL) compared with the placebo group (21·9 [20·2–23·7; ST2] to 24·3 [22·1–26·7; ST6] units per mL; p<0·0001 for all comparisons); GMTs were also significantly higher in the VLA15 M0-2-6 group than in the VLA15 M0-6 group (all p<0·0001 except for ST2 [p=0·0010] and ST3 [p=0·011]). Among VLA15 recipients, GMTs were highest in children followed by adolescents and then adults. Solicited local adverse events after any vaccination occurred more frequently among VLA15 recipients (M0-2-6, 178 [94%; 95% CI 89–96] of 190; M0-6, 176 [94%; 90–97] of 187) than placebo recipients (71 [34%; 28–41] of 208; p<0·0001 for both comparisons); the same was true for solicited systemic adverse events (M0-2-6, 128 [67%; 95% CI 60–74] of 190, p=0·0015 vs placebo; M0-6, 128 [68%; 61–75] of 187, p=0·0007 vs placebo; placebo, 107 [51%; 45–58] of 208). Most solicited adverse events were mild or moderate in severity; none was grade 4. There were no significant differences in the frequencies of unsolicited adverse events, related unsolicited adverse events, unsolicited serious adverse events (serious adverse events), and adverse events of special interest across groups in the overall population. None of the severe unsolicited adverse events, serious adverse events, or adverse events of special interest were considered related to vaccination and no deaths occurred through to month 12 of the trial. These findings confirm previously observed safety and immunogenicity profiles of VLA15 in adults and extend them to children aged 5 years and older and adolescents. The greater immunogenicity of VLA15 among children and adolescents might translate to increased flexibility in the real-world clinical setting. Pfizer and Valneva.

Incidence rates of Lyme borreliosis, a tickborne disease attributed to infection by Borrelia species, are increasing, and limitations to existing treatments potentiate the possibility of severe outcomes. Nevertheless, there are no licensed vaccines for Lyme borreliosis prevention in humans. This study investigated the immunogenicity and safety of a booster dose of VLA15, an investigational outer surface protein A (OspA)-based Lyme borreliosis vaccine that has previously shown safety and immunogenicity when administered as a primary vaccination series, following a primary VLA15 vaccination series. We report the results of the booster phase of a randomised, observer-blinded, placebo-controlled, multicentre, phase 2 study that enrolled healthy adults aged 18–65 years from five US clinical study centres to receive 135 μg or 180 μg VLA15 or placebo at months 0, 2, and 6 in the main study phase. Participants who received 180 μg VLA15 in the main study phase and did not have relevant protocol deviations were eligible for the booster phase (months 18–30). Participants were randomly reassigned (2:1) to receive an intramuscular injection of a VLA15 booster or placebo 1 year after the completion of primary vaccination (month 18) via a randomisation list generated by an unmasked statistician with a block size of six. Individuals involved in data safety monitoring, rerandomisation, vaccine handling, and vaccine accountability were unmasked; the study sponsor and statisticians were only unmasked after analysis of data up to 1 month after booster administration. All other individuals remained masked throughout the booster phase. The outcomes for the booster phase were the immunogenicity (evaluated in the booster per-protocol population) and safety (evaluated for all participants who received the booster) of the booster dose up to month 30. The study is registered at ClinicalTrials.gov (NCT03970733) and is completed. Between Feb 4 and March 23, 2021, 58 participants (28 men and 30 women) were screened, randomly assigned, and received VLA15 (n=39) or placebo (n=19). One participant in the placebo group was lost to follow-up. The IgG geometric mean titres for each OspA serotype (serotypes 1–6) in the VLA15 group peaked at 1 month after the booster dose (1277·0 U/mL [95% CI 861·8–1892·3] to 2194·5 U/mL [1566·8–3073·7] vs 23·6 U/mL [18·1–30·8] to 36·8 U/mL [26·4–51·3] in the placebo group [p<0·0001 for all serotypes]), remained elevated at month 24 (137·4 U/mL [95·8–196·9] to 265·8 U/mL [202·9–348·2] vs 22·3 U/mL [17·7–28·0] to 29·1 U/mL [20·8–40·6] in the placebo group; p<0·0001 for all serotypes), and declined by month 30 (54·1 U/mL [38·6–75·7] to 101·6 U/mL [77·6–133·1] vs 21·9 U/mL [18·0–26·6] to 24·9 U/mL [19·0–32·6] in the placebo group; p<0·0001 for all serotypes except serotype 1 [p=0·0006]). Solicited local adverse events were reported more frequently in the VLA15 group (35 [92%, 95% CI 79–97] of 38 participants) than the placebo group (six [32%, 15–54] of 19 participants; p<0·0001) after booster vaccination. There was no significant difference in the frequency of solicited systemic adverse events between groups (20 [59%, 42–74] of 34 participants in the VLA15 group vs six [38%, 18–61] of 16 participants in the placebo group). Related unsolicited adverse events (none severe) were reported by two (5%, 1–17) of 39 participants in the VLA15 group and none (0%, 0–17) of 19 participants in the placebo group. There were no severe solicited local or systemic adverse events or deaths during the study. A booster dose of VLA15 is safe and induces substantial anamnestic immune responses against all six OspA serotypes. As with previously investigated OspA-based Lyme borreliosis vaccines, waning immune responses were observed with VLA15, and annual boosters might therefore be required. Valneva.

In the nation-wide double-blind cluster-randomised Finnish Invasive Pneumococcal disease trial (FinIP, ClinicalTrials.gov NCT00861380, NCT00839254), we assessed the indirect impact of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against five pneumococcal disease syndromes. Children 6 weeks to 18 months received PHiD-CV10 in 48 clusters or hepatitis B/A-vaccine as control in 24 clusters according to infant 3+1/2+1 or catch-up schedules in years 2009-2011. Outcome data were collected from national health registers and included laboratory-confirmed and clinically suspected invasive pneumococcal disease (IPD), hospital-diagnosed pneumonia, tympanostomy tube placements (TTP) and outpatient antimicrobial prescriptions. Incidence rates in the unvaccinated population in years 2010-2015 were compared between PHiD-CV10 and control clusters in age groups <5 and ≥5 years (5-7 years for TTP and outpatient antimicrobial prescriptions), and in infants <3 months. PHiD-CV10 was introduced into the Finnish National Vaccination Programme (PCV-NVP) for 3-month-old infants without catch-up in 9/2010. From 2/2009 to 10/2010, 45398 children were enrolled. Vaccination coverage varied from 29 to 61% in PHiD-CV10 clusters. We detected no clear differences in the incidence rates between the unvaccinated cohorts of the treatment arms, except in single years. For example, the rates of vaccine-type IPD, non-laboratory-confirmed IPD and empyema were lower in PHiD-CV10 clusters compared to control clusters in 2012, 2015 and 2011, respectively, in the age-group ≥5 years. This is the first report from a clinical trial evaluating the indirect impact of a PCV against clinical outcomes in an unvaccinated population. We did not observe consistent indirect effects in the PHiD-CV10 clusters compared to the control clusters. We consider that the sub-optimal trial vaccination coverage did not allow the development of detectable indirect effects and that the supervening PCV-NVP significantly diminished the differences in PHiD-CV10 vaccination coverage between the treatment arms.

Neisseria meningitidis serogroup B is a major cause of invasive meningococcal disease, but a broadly protective vaccine is not currently licensed. A bivalent recombinant factor H-binding protein vaccine (recombinant lipoprotein 2086) has been developed to provide broad coverage against diverse invasive meningococcus serogroup B strains. Our aim was to test the immune response of this vaccine. This randomised, placebo-controlled trial enrolled healthy adolescents from 25 sites in Australia, Poland, and Spain. Exclusion criteria were previous invasive meningococcal disease or serogroup B vaccination, previous adverse reaction or known hypersensitivity to the vaccine, any significant comorbidities, and immunosuppressive therapy or receipt of blood products in the past 6 months. Participants were randomly assigned with a computerised block randomisation scheme to receive ascending doses of vaccine (60, 120, or 200 μg) or placebo at 0, 2, and 6 months. Principal investigators, participants and their guardians, and laboratory personnel were masked to the allocation; dispensing staff were not. Immunogenicity was measured by serum bactericidal assays using human complement (hSBA) against eight diverse meningococcus serogroup B strains. The co-primary endpoints were seroconversion for the two indicator strains (PMB1745 and PMB17) analysed by the Clopper-Pearson method. Local and systemic reactions and adverse events were recorded. The study is registered at ClinicalTrials.gov, number NCT00808028. 539 participants were enrolled and 511 received all three study vaccinations—116 in the placebo group, 21 in the 60 μg group, 191 in the 120 μg group, and 183 in the 200 μg group. The proportion of participants responding with an hSBA titre equal to or greater than the lower limit of quantitation of the hSBA assays (reciprcocal titres of 7 to 18, depending on test strain) was similar for the two largest doses and ranged from 75·6 to 100·0% for the 120 μg dose and 67·9 to 99·0% for the 200 μg dose. Seroconversion for the PMB1745 reference strain was 17 of 19 (89·5%) participants for the 60 μg dose, 103 of 111 (92·8%) participants for the 120 μg dose, 94 of 100 (94·0%) participants for the 200 μg dose, and four of 73 (5·5%) participants for placebo. For the PMB17 reference strain seroconversion was 17 of 21 (81·0%) participants for the 60 μg dose, 97 of 112 (86·6%) participants for the 120 μg dose, 89 of 105 (84·8%) participants for the 200 μg dose, and one of 79 (1·3%) participants for placebo. The hSBA response was robust as shown by the high proportion of responders at hSBA titres up to 16. Mild-to-moderate injection site pain was the most common local reaction (50 occurrences with the 60 μg dose, 437 with the 120 μg dose, 464 with the 200 μg dose, and 54 with placebo). Systemic events, including fatigue and headache, were generally mild to moderate. Overall, adverse events were reported by 18 participants (81·8%) in the 60 μg group, 77 (38·9%) in the 120 μg group, 92 (47·2%) in the 200 μg group, and 54 (44·6%) in the placebo group. Fevers were rare and generally mild (one in the 60 μg group, 24 in the 120 μg group, 35 in the 200 μg group, and five in the placebo group; range, 0–6·3% after each dose). Incidence and severity of fever did not increase with subsequent vaccine dose within groups. One related serious adverse event that resolved without sequelae occurred after the third dose (200 μg). The bivalent recombinant lipoprotein 2086 vaccine is immunogenic and induces robust hSBA activity against diverse invasive meningococcus serogroup B disease strains and the vaccine is well tolerated. Recombinant lipoprotein 2086 vaccine is a promising candidate for broad protection against invasive meningococcus serogroup B disease. Wyeth, Pfizer.

•Streptococcus pneumoniae constitute a major global public health problem.•PnuBioVax, a novel multi-antigen protein vaccine against Streptococcus pneumoniae.•PnuBioVax is safe and immunogenic in healthy adult subjects: Phase 1 trial results. Pneumococcal vaccines, combining multiple protein antigens, provide an alternative approach to currently marketed vaccines and may provide broader protection against pneumococcal disease. This trial evaluated the safety and immunogenicity of a novel vaccine candidate PnuBioVax in healthy young adults. In a Phase 1 double-blind study, 36 subjects (18–40 years) were randomised to receive 3 doses of PnuBioVax, 28 days apart, at one of three dose levels (50, 200, 500 µg) or placebo. Safety assessments included rates of emergent adverse events (AEs), injection site and systemic reactions. Immunogenicity endpoints included antibody titre against PnuBioVax and selected pneumococcal antigens. In the placebo (n=9) and PnuBioVax (n=27) vaccinated subjects, there were 15 and 72, reported TEAEs, respectively. The majority of TEAEs were classified as common vaccine related AEs. There were no serious AEs. Common vaccine-related AEs occurred in 13 PnuBioVax (48%) and 2 placebo (22%) subjects and were all headaches (mild and moderate). Injection site reactions, mostly pain and tenderness (graded mild or moderate) were reported, in particular in the 200 µg and 500 µg PnuBioVax groups. There were no clinically significant changes in vital signs, ECG or blood chemistries. Subjects receiving the higher dose (200 and 500 μg) demonstrated a greater fold increase in IgG titre compared with the starting dose (50 μg) or the placebo group. The fold-increase was statistically significantly higher for 200 and 500µg PnuBioVax vs 50µg PnuBioVax and placebo at each timepoint post-immunisation. Most subjects receiving 200 and 500 µg PnuBioVax demonstrated a ≥2-fold increase in antibody against pneumolysin (Ply), Pneumococcal surface antigen (PsaA), PiaA (Pneumococcal iron acquisition), PspA (Pneumococcal surface protein A) and pilus proteins (RrgB and RrgA). All dose levels were considered safe and well tolerated. There was a statistically significant increase in anti-PnuBioVax IgG titres at the 200 and 500 µg dose levels compared to 50 µg and placebo. Trial registration number: NCT02572635https://www.clinicaltrials.gov.

Acute otitis media is one of the most commonly-diagnosed childhood infections. This study assessed the efficacy of a novel vaccine that contained polysaccharides from 11 different Streptococcus pneumoniae serotypes each conjugated to Haemophilus influenzae-derived protein D in prevention of acute otitis media. 4968 infants were randomly assigned to receive either pneumococcal protein D conjugate or hepatitis A vaccine at the ages of 3, 4, 5, and 12–15 months and were followed-up until the end of the second year of life. Middle-ear fluid was obtained for bacteriological culture and serotyping in children who presented with abnormal tympanic membrane or presence of middle-ear effusion, plus two predefined clinical symptoms. The primary endpoint was protective efficacy against the first episode of acute otitis media caused by vaccine pneumococcal serotypes. Analysis was per protocol. From 2 weeks after the third dose to 24–27 months of age, 333 clinical episodes of acute otitis media were recorded in the protein D conjugate group (n=2455) and 499 in the control group (n=2452), giving a significant (33·6% [95% CI 20·8–44·3]) reduction in the overall incidence of acute otitis media. Vaccine efficacy was shown for episodes of acute otitis media caused by pneumococcal vaccine serotypes (52·6% [35·0–65·5] for the first episode and 57·6% [41·4–69·3] for any episode). Efficacy was also shown against episodes of acute otitis media caused by non-typable H influenzae (35·3% [1·8–57·4]). The vaccine reduced frequency of infection from vaccine-related cross-reactive pneumococcal serotypes by 65·5%, but did not significantly change the number of episodes caused by other non-vaccine serotypes. These results confirm that using the H influenzae-derived protein D as a carrier protein for pneumococcal polysaccharides not only allowed protection against pneumococcal otitis, but also against acute otitis media due to non-typable H influenzae. Whether this approach would also allow improved protection against lower respiratory tract infections warrants further investigation.

Antimicrobial drugs are frequently prescribed to children for respiratory tract infections such as otitis, tonsillitis, sinusitis, and pneumonia. We assessed the effect of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; GlaxoSmithKline) on antimicrobial purchases. In this nationwide phase 3–4 cluster-randomised, double-blind trial, children younger than 19 months were randomly assigned to receive PHiD-CV10 in 52 of 78 clusters or hepatitis B or A vaccine as control in 26 clusters according to three plus one or two plus one schedules (infants younger than 7 months) or catch-up schedules (children aged 7–18 months). The main objective for the antimicrobial treatment outcome was to assess vaccine effectiveness against outpatient prescriptions of antimicrobial drugs recommended by national treatment guidelines for acute otitis media in Finland in children who received at least one dose of study vaccine before 7 months of age. Masked follow-up lasted from the date of first vaccination (from Feb 18, 2009, through Oct 5, 2010) to Dec 31, 2011. We obtained data on all purchased antimicrobial prescriptions through the benefits register of the Social Insurance Institution of Finland. This and the nested acute otitis media trial are registered at ClinicalTrials.gov, numbers NCT00861380 and NCT00839254. More than 47 000 children were enrolled. In 30 527 infants younger than 7 months at enrolment, 98 436 outpatient antimicrobial purchases were reported with incidence of 1·69 per person-year in the control clusters. Analysis of the main objective included 91% of all antimicrobial purchases: 31 982 in the control and 57 964 in the PHiD-CV10 clusters. Vaccine effectiveness was 8% (95% CI 1–14) and the incidence rate difference 0·12 per person-year corresponding to the number needed to vaccinate of five (95% CI 3–67) to prevent one purchase during the 2 year follow-up for combined PHiD-CV10 three plus one and two plus one infant schedules. The vaccine effectiveness was identical for the two infant schedules. In the catch-up schedules, the vaccine effectiveness was 3% (95% CI −4 to 10). Despite low relative rate reductions the absolute rate reductions were substantial because of the high incidence of the outcome. This reduction would lead to over 12 000 fewer antimicrobial purchases per year in children younger than 24 months in Finland (birth cohort of 60 000 children). GlaxoSmithKline Biologicals SA and National Institute for Health and Welfare (THL), Finland.

Lyme borreliosis is caused by Borrelia burgdorferi sensu stricto in the USA and by several Borrelia species in Europe and Asia, but no human vaccine is available. We investigated the safety and immunogenicity of adjuvanted and non-adjuvanted vaccines containing protective epitopes from Borrelia species outer surface protein A (OspA) serotypes in healthy adults. Between March 1, 2011, and May 8, 2012, we did a double-blind, randomised, dose-escalation phase 1/2 study at four sites in Austria and Germany. Healthy adults aged 18–70 years who were seronegative for B burgdorferi sensu lato were eligible for inclusion. Participants were recruited sequentially and randomly assigned to one of six study groups in equal ratios via an electronic data capture system. Participants and investigators were masked to group allocation. Participants received three vaccinations containing 30 μg, 60 μg, or 90 μg OspA antigen with or without an adjuvant, with intervals of 28 days, and a booster 9–12 months after the first immunisation. The coprimary endpoints were the frequency and severity of injection-site and systemic reactions within 7 days of each vaccination, and the antibody responses to OspA serotypes 1–6, as established by ELISA. This study is registered with ClinicalTrials.gov, number NCT01504347. 300 participants were randomly assigned: 151 to adjuvanted vaccines (50 to 30 μg, 51 to 60 μg, and 50 to 90 μg doses), and 149 to non-adjuvanted vaccines (50 to 30 μg, 49 to 60 μg, and 50 to 90 μg doses). Adverse reactions were predominantly mild, and no vaccine-related serious adverse events were reported. The risk of systemic reactions (risk ratio 0·54 [95% CI 0·41–0·70]; p<0·0001) and of moderate or severe systemic reactions (0·35 [0·13–0·92]; p=0·034) was significantly lower for adjuvanted than non-adjuvanted formulations. The 30 μg adjuvanted formulation had the best tolerability profile; only headache (five [10%, 95% CI 4–20] of 50), injection-site pain (16 [32%, 21–45]), and tenderness (17 [34%, 23–47]) affected more than 6% of patients. All doses and formulations induced substantial mean IgG antibody titres against OspA serotypes 1–6 after the first three vaccinations (range 6944–17 321) and booster (19 056–32 824) immunisations. The 30 μg adjuvanted formulation induced the highest antibody titres after the booster: range 26 143 (95% CI 18 906–36 151) to 42 381 (31 288–57 407). The novel multivalent OspA vaccine could be an effective intervention for prevention of Lyme borreliosis in Europe and the USA, and possibly worldwide. Larger confirmatory formulation studies will need to be done that include individuals seropositive for Borrelia burgdorferi sensu lato before placebo-controlled phase 3 efficacy studies can begin. Baxter.