Summary Background Rotavirus gastroenteritis causes many deaths in infants in sub-Saharan Africa. Because rotavirus vaccines have proven effective in developed countries but had not been tested in ...developing countries, we assessed efficacy of a pentavalent rotavirus vaccine against severe disease in Ghana, Kenya, and Mali between April, 2007, and March, 2009. Methods In our multicentre, double-blind, placebo-controlled trial, undertaken in rural areas of Ghana and Kenya and an urban area of Mali, we randomly assigned infants aged 4–12 weeks without symptoms of gastrointestinal disorders in a 1:1 ratio to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks, 10 weeks, and 14 weeks of age. Infants with HIV infection were not excluded. Randomisation was done by computer-generated randomisation sequence in blocks of six. We obtained data for gastrointestinal symptoms from parents on presentation to health-care facilities and clinical data were obtained prospectively by clinicians. The primary endpoint was severe rotavirus gastroenteritis (Vesikari score ≥11), detected by enzyme immunoassay, arising 14 days or more after the third dose of placebo or vaccine to end of study (March 31, 2009; around 21 months of age). Analysis was per protocol; infants who received scheduled doses of vaccine or placebo without intervening laboratory-confirmed naturally occurring rotavirus disease earlier than 14 days after the third dose and had complete clinical and laboratory results were included in the analysis. This study is registered with ClinicalTrials.gov , number NCT00362648. Findings 5468 infants were randomly assigned to receive pentavalent rotavirus vaccine (n=2733) or placebo (n=2735). 2357 infants assigned to vaccine and 2348 assigned to placebo were included in the per-protocol analysis. 79 cases of severe rotavirus gastroenteritis were reported in 2610·6 person-years in the vaccine group, compared with 129 cases in 2585·9 person-years in the placebo group, resulting in a vaccine efficacy against severe rotavirus gastroenteritis of 39·3% (95% CI 19·1–54·7, p=0·0003 for efficacy >0%). Median follow-up in both groups was 527 days starting 14 days after the third dose of vaccine or placebo was given. 42 (1·5%) of 2723 infants assigned to receive vaccine and 45 (1·7%) of 2724 infants assigned to receive placebo had a serious adverse event within 14 days of any dose. The most frequent serious adverse event was gastroenteritis (vaccine 17 0·6%; placebo 17 0·6%). Interpretation Pentavalent rotavirus vaccine is effective against severe rotavirus gastroenteritis in the first 2 years of life in African countries with high mortality in infants younger than 5 years. We support WHO's recommendation for adoption of rotavirus vaccine into national expanded programmes on immunisation in Africa. Funding PATH (GAVI Alliance grant) and Merck.
Summary Background Rotavirus vaccine has proved effective for prevention of severe rotavirus gastroenteritis in infants in developed countries, but no efficacy studies have been done in developing ...countries in Asia. We assessed the clinical efficacy of live oral pentavalent rotavirus vaccine for prevention of severe rotavirus gastroenteritis in infants in Bangladesh and Vietnam. Methods In this multicentre, double-blind, placebo-controlled trial, undertaken in rural Matlab, Bangladesh, and urban and periurban Nha Trang, Vietnam, infants aged 4–12 weeks without symptoms of gastrointestinal disorders were randomly assigned (1:1) to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks, 10 weeks, and 14 weeks of age, in conjunction with routine infant vaccines including oral poliovirus vaccine. Randomisation was done by computer-generated randomisation sequence in blocks of six. Episodes of gastroenteritis in infants who presented to study medical facilities were reported by clinical staff and from parent recollection. The primary endpoint was severe rotavirus gastroenteritis (Vesikari score ≥11) arising 14 days or more after the third dose of placebo or vaccine to end of study (March 31, 2009; around 21 months of age). Analysis was per protocol; infants who received scheduled doses of vaccine or placebo without intervening laboratory-confirmed naturally occurring rotavirus disease earlier than 14 days after the third dose and had complete clinical and laboratory results were included in the analysis. This study is registered with ClinicalTrials.gov , number NCT00362648. Findings 2036 infants were randomly assigned to receive pentavalent rotavirus vaccine (n=1018) or placebo (n=1018). 991 infants assigned to pentavalent rotavirus vaccine and 978 assigned to placebo were included in the per-protocol analysis. Median follow up from 14 days after the third dose of placebo or vaccine until final disposition was 498 days (IQR 480–575). 38 cases of severe rotavirus gastroenteritis (Vesikari score ≥11) were reported during more than 1197 person-years of follow up in the vaccine group, compared with 71 cases in more than 1156 person years in the placebo group, resulting in a vaccine efficacy of 48·3% (95% CI 22·3–66·1) against severe disease (p=0·0005 for efficacy >0%) during nearly 2 years of follow-up. 25 (2·5%) of 1017 infants assigned to receive vaccine and 20 (2·0%) of 1018 assigned to receive placebo had a serious adverse event within 14 days of any dose. The most frequent serious adverse event was pneumonia (vaccine 12 1·2%; placebo 15 1·5%). Interpretation In infants in developing countries in Asia, pentavalent rotavirus vaccine is safe and efficacious against severe rotavirus gastroenteritis, and our results support expanded WHO recommendations to promote its global use. Funding PATH (GAVI Alliance grant) and Merck.
Summary Background Despite preventive vaccines for oncogenic human papillomaviruses (HPVs), cervical intraepithelial neoplasia (CIN) is common, and current treatments are ablative and can lead to ...long-term reproductive morbidity. We assessed whether VGX-3100, synthetic plasmids targeting HPV-16 and HPV-18 E6 and E7 proteins, delivered by electroporation, would cause histopathological regression in women with CIN2/3. Methods Efficacy, safety, and immunogenicity of VGX-3100 were assessed in CIN2/3 associated with HPV-16 and HPV-18, in a randomised, double-blind, placebo-controlled phase 2b study. Patients from 36 academic and private gynaecology practices in seven countries were randomised (3:1) to receive 6 mg VGX-3100 or placebo (1 mL), given intramuscularly at 0, 4, and 12 weeks. Randomisation was stratified by age (<25 vs ≥25 years) and CIN2 versus CIN3 by computer-generated allocation sequence (block size 4). Funder and site personnel, participants, and pathologists were masked to treatment. The primary efficacy endpoint was regression to CIN1 or normal pathology 36 weeks after the first dose. Per-protocol and modified intention-to-treat analyses were based on patients receiving three doses without protocol violations, and on patients receiving at least one dose, respectively. The safety population included all patients who received at least one dose. The trial is registered at ClinicalTrials.gov (number NCT01304524 ) and EudraCT (number 2012-001334-33). Findings Between Oct 19, 2011, and July 30, 2013, 167 patients received either VGX-3100 (n=125) or placebo (n=42). In the per-protocol analysis 53 (49·5%) of 107 VGX-3100 recipients and 11 (30·6%) of 36 placebo recipients had histopathological regression (percentage point difference 19·0 95% CI 1·4–36·6; p=0·034). In the modified intention-to-treat analysis 55 (48·2%) of 114 VGX-3100 recipients and 12 (30·0%) of 40 placebo recipients had histopathological regression (percentage point difference 18·2 95% CI 1·3–34·4; p=0·034). Injection-site reactions occurred in most patients, but only erythema was significantly more common in the VGX-3100 group (98/125, 78·4%) than in the placebo group (24/42, 57·1%; percentage point difference 21·3 95% CI 5·3–37·8; p=0·007). Interpretation VGX-3100 is the first therapeutic vaccine to show efficacy against CIN2/3 associated with HPV-16 and HPV-18. VGX-3100 could present a non-surgical therapeutic option for CIN2/3, changing the treatment outlook for this common disease. Funding Inovio Pharmaceuticals.
Pediatric use of pneumococcal conjugate vaccines (PCV) has been associated with significant decrease in disease burden. However, disease caused by non-vaccine serotypes has increased. Safety and ...immunogenicity of 15-valent PCV (PCV15) containing serotypes included in 13-valent PCV (PCV13) plus serotypes 22F and 33F were evaluated in infants (NCT01215188).
Infants received adjuvanted PCV15, nonadjuvanted PCV15, or PCV13 at 2, 4, 6, and 12–15 months of age. Safety was monitored for 14 days after each dose. Serotype-specific IgG geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were measured at postdose-3, predose-4, and postdose-4.
Safety profiles were comparable across vaccination groups. At postdose-3, both PCV15 formulations were non-inferior to PCV13 for 10 of 13 shared serotypes but failed non-inferiority for 3 serotypes (6A, 6B, and 19A) based on proportion of subjects achieving IgG GMC ≥0.35 µg/mL. Adjuvanted PCV15 and nonadjuvanted PCV15 were non-inferior to PCV13 for 11 and 8 shared serotypes, respectively, based on postdose 3 comparisons of GMC ratios. PCV15 induced higher antibodies to serotypes 3, 22F, and 33F than PCV13.
PCV15 displayed acceptable safety profile and induced IgG and OPA to all 15 vaccine serotypes at levels comparable to PCV13 for 10 of 13 shared serotypes.
Study identification: V114-003.
CLINICALTRIALS.GOV identifier: NCT01215188.
Clinical responses with programmed death (PD-1) receptor-directed antibodies occur in about 20% of patients with advanced head and neck squamous cell cancer (HNSCCa). Viral neoantigens, such as the ...E6/E7 proteins of HPV16/18, are attractive targets for therapeutic immunization and offer an immune activation strategy that may be complementary to PD-1 inhibition.
We report phase Ib/II safety, tolerability, and immunogenicity results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 with IL12 encoding plasmids) delivered by electroporation with CELLECTRA constant current device. Twenty-two patients with locally advanced, p16
HNSCCa received MEDI0457.
MEDI0457 was associated with mild injection site reactions, but no treatment-related grade 3-5 adverse events (AE) were noted. Eighteen of 21 evaluable patients showed elevated antigen-specific T-cell activity by IFNγ ELISpot, and persistent cellular responses surpassing 100 spot-forming units (SFUs)/10
peripheral blood mononuclear cells (PBMCs) were noted out to 1 year. Induction of HPV-specific CD8
T cells was observed. MEDI0457 shifted the CD8
/FoxP3
ratio in 4 of 5 post immunotherapy tumor samples and increased the number of perforin
immune infiltrates in all 5 patients. One patient developed metastatic disease and was treated with anti-PD-1 therapy with a rapid and durable complete response. Flow-cytometric analyses revealed induction of HPV16-specific PD-1
CD8
T cells that were not found prior to MEDI0547 (0% vs. 1.8%).
These data demonstrate that MEDI0457 can generate durable HPV16/18 antigen-specific peripheral and tumor immune responses. This approach may be used as a complementary strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve therapeutic outcomes.
Widespread use of 7-valent pneumococcal conjugate vaccine (PCV7) in children has led to significant reduction in pneumococcal disease in children and adults. However, diseases caused by serotypes not ...included in PCV7 have increased. A 15-valent pneumococcal conjugate vaccine (PCV15) containing serotypes in PCV7 and 8 additional serotypes (1, 3, 5, 6A, 7F, 19A, 22F, 33F) was developed and evaluated in toddlers 12 to 15 months of age.
Ninety toddlers who completed an infant series with PCV7 received a single dose of either aluminum-adjuvanted PCV15, nonadjuvanted PCV15, or PCV7. Injection-site and systemic adverse events (AEs) were collected for 14 days postvaccination and serious AEs (SAEs) were collected for 30 days postvaccination. Solicited AEs included local (pain/tenderness, swelling, nodule and redness) and systemic (fatigue, arthralgia and myalgia) AEs. Serotype-specific immunoglobulin G (IgG) and opsonophagocytic (OPA) responses were measured immediately prior and 30 days postvaccination.
Incidences of local and systemic AEs were comparable across vaccine groups. The majority of reported events, regardless of vaccine received, were transient and of mild to moderate intensity. No clinically significant differences were observed when comparing duration and severity of AEs. No vaccine-related SAEs or discontinuations from the study due to AEs were reported. Pneumococcal IgG concentrations and OPA titers increased postvaccination, with appreciable fold rises for all serotypes. Antibody levels were comparable between both PCV15 formulations and generally comparable to PCV7 for the shared serotypes.
Both formulations of PCV15 display acceptable safety profiles and induce IgG and OPA responses to all vaccine serotypes.
VGX-3100 is an investigational DNA-based immunotherapy being developed as an alternative to surgery and ablation for cervical High-Grade Squamous Intraepithelial Lesion (HSIL) with the aim of ...preserving reproductive health while treating precancerous disease. Response durability up to 1.5 y following dosing is now reported.
Histologic regression and HPV16 and/or HPV 18 (HPV16/18) clearance were previously demonstrated in a randomized, placebo-controlled, double-blind trial and reported for 6 months after the last dose of VGX-3100 or placebo. The presence of HPV16/18, Pap smear diagnoses, and immunogenicity longer-term responses were assessed at 18 months after the last dose.
91% (32/35) VGX-3100-treated women, whose cervical HSIL regressed and avoided excision at 6 months following study treatment completion, had no detectable HPV16/18 at 18 months following treatment completion. These results were comparable to those for women who received placebo and then later underwent surgery. For VGX-3100 recipients who regressed at 6 months following study treatment completion and avoided excision during the trial, Pap testing showed no HSIL recurrence at 18 months following VGX-3100 treatment. VGX-3100-induced cellular immune responses specific for HPV 16/18 E6/E7 remained higher than for placebo control recipients at 18 months.
In women with cervical HSIL who responded to VGX-3100 and were able to avoid surgery, clinical outcomes were comparable to the placebo control group which underwent conventional surgical treatment. These findings extend the understanding of the durability of the treatment effect of VGX-3100 up to 1.5 y and support that VGX-3100 could be used as an alternative to surgery.
BACKGROUND:Premature infants seem to be at greater risk of hospitalization from rotavirus gastroenteritis than term infants. Safety and efficacy of the pentavalent human-bovine (WC3) reassortant ...rotavirus vaccine were assessed in premature infants enrolled in the large-scale, blinded, placebo-controlled rotavirus efficacy and safety trial (REST).
METHODS:Healthy infants 6–12 weeks of chronologic age at study entry were randomized to receive 3 oral doses of pentavalent rotavirus vaccine or placebo at 4- to 10-week intervals. Infants born at ≤36 weeks of gestational age were eligible if thriving at the time of enrollment. Safety and efficacy were retrospectively assessed in these premature infants comparing vaccine with placebo recipients. Cases of rotavirus gastroenteritis were defined as forceful vomiting and/or ≥3 watery or looser-than-normal stools within a 24-hour period, accompanied by detection of rotavirus antigen in the stool.
RESULTS:A total of 2070 infants between 25 and 36 gestational weeks received at least 1 dose of vaccine or placebo; 1005 vaccine recipients and 1061 placebo recipients were evaluable for safety. Serious adverse events occurred in 55 vaccine recipients (5.5%) and 62 placebo recipients (5.8%). In a nested substudy of 308 premature infants evaluable for detailed safety (154 in each group), the frequencies of fever, diarrhea, vomiting, and irritability were comparable between vaccine and placebo recipients. Overall, 3 doses of the pentavalent vaccine reduced the rate of hospitalizations and emergency department visits in premature infants due to rotavirus gastroenteritis by 100% (95% CI82.2–100) compared with placebo. The vaccine also prevented 73.0% (95% CI−2.2–95.2) of rotavirus gastroenteritis cases of any severity.
CONCLUSIONS:In this post hoc analysis of healthy premature infants, the pentavalent rotavirus vaccine was generally well-tolerated and substantially reduced rotavirus-attributable hospitalizations and emergency department visits compared with placebo. Overall, vaccine safety and efficacy seemed to be generally comparable to the results in the REST study population as a whole. These results support vaccinating healthy premature infants on the same schedule as term infants.
Rotavirus is the leading cause of dehydrating acute gastroenteritis in infants worldwide. Previous studies of a live pentavalent human-bovine reassortant rotavirus vaccine have shown it to be ...efficacious across a range of potencies.
Our goal was to evaluate the efficacy, immunogenicity, and safety of pentavalent rotavirus vaccine at the end of shelf life in healthy infants.
During 2002-2004, 1312 healthy infants approximately 6 to 12 weeks old from the United States (47%) and Finland (53%) were randomly assigned to receive 3 oral doses of vaccine (vaccine at approximately 1.1 x 10(7) infectious U per dose) or placebo approximately 4 to 10 weeks apart. Infants were to be followed for acute gastroenteritis through 1 rotavirus season after vaccination and for adverse events postvaccination.
Three doses of pentavalent rotavirus vaccine at the end of shelf life demonstrated efficacy against rotavirus gastroenteritis caused by human G-serotypes included in the vaccine (G1-G4). Efficacy against severe rotavirus gastroenteritis was 100%, and efficacy against any rotavirus gastroenteritis regardless of severity was 72.5%. A threefold rise in G1 serum neutralizing was observed in 57% and in anti-rotavirus immunoglobulin A in 96% of pentavalent rotavirus vaccine recipients. No statistically significant increase in vomiting, diarrhea, or irritability was observed among pentavalent rotavirus vaccine recipients compared with placebo recipients within the 7-day period from each dose. A statistically significant increase in fevers (> or = 100.5 degrees F, rectal equivalent) was observed among pentavalent rotavirus vaccine recipients compared with placebo recipients after dose 1.
This pentavalent human-bovine rotavirus vaccine was generally well tolerated, efficacious, and immunogenic at the end of shelf life.
Highlights ► We report immunogenicity of the pentavalent rotavirus vaccine in African infants. ► Serum IgA sero-conversion was good and consistent in infants across 3 African sites. ► Serum IgA ...responses and GMTs were lower than that seen in developed settings.
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