SARS-CoV-2 DNA Vaccine INO-4800 Induces Durable Immune Responses Capable of Being Boosted in a Phase 1 Open-Label Trial.

BACKGROUND: Additional severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines that are safe and effective as primary vaccines and boosters remain urgently needed to combat the coronavirus disease 2019 (COVID-19) pandemic. We describe safety and durability of immune responses following 2 primary doses and a homologous booster dose of an investigational DNA vaccine (INO-4800) targeting full-length spike antigen. METHODS: Three dosage strengths of INO-4800 (0.5 mg, 1.0 mg, and 2.0 mg) were evaluated in 120 age-stratified healthy adults. Intradermal injection of INO-4800 followed by electroporation at 0 and 4 weeks preceded an optional booster 6-10.5 months after the second dose. RESULTS: INO-4800 appeared well tolerated with no treatment-related serious adverse events. Most adverse events were mild and did not increase in frequency with age and subsequent dosing. A durable antibody response was observed 6 months following the second dose; a homologous booster dose significantly increased immune responses. Cytokine-producing T cells and activated CD8+ T cells with lytic potential were significantly increased in the 2.0-mg dose group. CONCLUSIONS: INO-4800 was well tolerated in a 2-dose primary series and homologous booster in all adults, including elderly participants. These results support further development of INO-4800 for use as primary vaccine and booster. CLINICAL TRIALS REGISTRATION: NCT04336410.

Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial.

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.

Interim Results of a Phase 1/2 Open-Label Study of INO-3107 for HPV-6 and/or HPV-11-Associated Recurrent Respiratory Papillomatosis.

OBJECTIVE: To evaluate the safety, immunogenicity, and efficacy of INO-3107, a DNA immunotherapy designed to elicit targeted T-cell responses against human papillomavirus (HPV) types 6 and 11, in adult patients with recurrent respiratory papillomatosis (RRP; NCT04398433). METHODS: Eligible patients required ≥2 surgical interventions for RRP in the year preceding dosing. INO-3107 was administered by intramuscular (IM) injection followed by electroporation (EP) on weeks 0, 3, 6, and 9. Patients underwent surgical debulking within 14 days prior to first dose, with office laryngoscopy and staging at screening and weeks 6, 11, 26, and 52. Primary endpoint was safety and tolerability, as assessed by treatment-emergent adverse events (TEAEs). Secondary endpoints included frequency of surgical interventions post-INO-3107 and cellular immune responses. RESULTS: An initial cohort of 21 patients was enrolled between October 2020 and August 2021. Fifteen (71.4%) patients had ≥1 TEAE; 11 (52.4%) were Grade 1, and 3 (14.3%) were Grade 3 (none treatment related). The most frequently reported TEAE was injection site or procedural pain (n = 8; 38.1%). Sixteen (76.2%) patients had fewer surgical interventions in the year following INO-3107 administration, with a median decrease of 3 interventions versus the preceding year. The RRP severity score, modified by Pransky, showed improvement from baseline to week 52. INO-3107 induced durable cellular responses against HPV-6 and HPV-11, with an increase in activated CD4 and CD8 T cells and CD8 cells with lytic potential. CONCLUSION: The data suggest that INO-3107 administered by IM/EP is tolerable and immunogenic and provides clinical benefit to adults with RRP. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:3087-3093, 2023.

Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial.

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 >or=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.

Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebo-controlled trial.

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 >or=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 >or=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.

Efficacy of the pentavalent rotavirus vaccine, RotaTeq® (RV5), between doses of a 3-dose series and with less than 3 doses (incomplete regimen).

Post-hoc analyses of the Rotavirus Efficacy and Safety Trial (REST) were conducted to determine whether the pentavalent rotavirus vaccine (RV5) confers early protection against rotavirus gastroenteritis (RVGE) before completion of the 3-dose regimen. To evaluate the efficacy of RV5 between doses in reducing the rates of RVGE-related hospitalizations and emergency department (ED) visits in infants who ultimately received all 3 doses of RV5/placebo, events occurring from 2 weeks after the first and second doses to receipt of the subsequent dose (Analysis A) and events occurring from 2 weeks after the first and second doses to 2 weeks after the subsequent dose (Analysis B) were analyzed. In Analysis A, RV5 reduced the rates of combined hospitalizations and ED visits for G1-G4 RVGE or RVGE regardless of serotype between doses 1 and 2 by 100% (95% confidence interval [CI]: 72-100%) or 82% (95% CI: 39-97%), respectively, and between doses 2 and 3, RV5 reduced the rates of combined hospitalizations and ED visits for G1-G4 RVGE or RVGE regardless of serotype by 91% (95% CI: 63-99%) or 84% (95% CI: 54-96%), respectively. Similar rate reductions were observed in Analysis B. These data suggest that RV5 provides a high level of protection between doses against hospitalizations and ED visits for RVGE starting as early as 14 days after the first dose.

Assessing non-inferiority to an aggregate response with an application to development of pneumococcal conjugate vaccines.

The development of a new pneumococcal conjugate vaccine involves assessing the responses of the new serotypes included in the vaccine. The World Health Organization guidance states that the response from each new serotype in the new vaccine should be compared with the aggregate response from the existing vaccine to evaluate non-inferiority. However, no details are provided on how to define and estimate the aggregate response and what methods to use for non-inferiority comparisons. We investigate several methods to estimate the aggregate response based on binary data including simple average, model-based, and lowest response methods. The response of each new serotype is then compared with the estimated aggregate response for non-inferiority. The non-inferiority test p-value and confidence interval are obtained from Miettinen and Nurminen's method, using an effective sample size. The methods are evaluated using simulations and demonstrated with a real clinical trial example.

Durability of response to VGX-3100 treatment of HPV16/18 positive cervical HSIL.

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.

Safety and immunogenicity of INO-4800 DNA vaccine against SARS-CoV-2: A preliminary report of an open-label, Phase 1 clinical trial.

BACKGROUND: A vaccine against SARS-CoV-2 is of high urgency. Here the safety and immunogenicity induced by a DNA vaccine (INO-4800) targeting the full length spike antigen of SARS-CoV-2 are described. METHODS: INO-4800 was evaluated in two groups of 20 participants, receiving either 1.0 mg or 2.0 mg of vaccine intradermally followed by CELLECTRA® EP at 0 and 4 weeks. Thirty-nine subjects completed both doses; one subject in the 2.0 mg group discontinued trial participation prior to receiving the second dose. ClinicalTrials.gov identifier: NCT04336410. FINDINGS: The median age was 34.5, 55% (22/40) were men and 82.5% (33/40) white. Through week 8, only 6 related Grade 1 adverse events in 5 subjects were observed. None of these increased in frequency with the second administration. No serious adverse events were reported. All 38 subjects evaluable for immunogenicity had cellular and/or humoral immune responses following the second dose of INO-4800. By week 6, 95% (36/38) of the participants seroconverted based on their responses by generating binding (ELISA) and/or neutralizing antibodies (PRNT IC50), with responder geometric mean binding antibody titers of 655.5 [95% CI (255.6, 1681.0)] and 994.2 [95% CI (395.3, 2500.3)] in the 1.0 mg and 2.0 mg groups, respectively. For neutralizing antibody, 78% (14/18) and 84% (16/19) generated a response with corresponding geometric mean titers of 102.3 [95% CI (37.4, 280.3)] and 63.5 [95% CI (39.6, 101.8)], in the respective groups. By week 8, 74% (14/19) and 100% (19/19) of subjects generated T cell responses by IFN-É£ ELISpot assay with the median SFU per 106 PBMC of 46 [95% CI (21.1, 142.2)] and 71 [95% CI (32.2, 194.4)] in the 1.0 mg and 2.0 mg groups, respectively. Flow cytometry demonstrated a T cell response, dominated by CD8+ T cells co-producing IFN-É£ and TNF-α, without increase in IL-4. INTERPRETATION: INO-4800 demonstrated excellent safety and tolerability and was immunogenic in 100% (38/38) of the vaccinated subjects by eliciting either or both humoral or cellular immune responses. FUNDING: Coalition for Epidemic Preparedness Innovations (CEPI).

Safety and immunogenicity of VGX-3100 formulations in a healthy young adult population.

HPV remains the most common sexually transmitted disease worldwide, despite improvements in awareness, screening, prophylactic vaccination uptake, and surgical treatment. VGX-3100 is an immunotherapy that uses electroporation to introduce DNA encoding for modified HPV-16 and HPV-18, E6-and E7 proteins into myocytes to stimulate an effector T cell response. We now report immunogenicity and safety of VGX-3100 for a refrigeration-stable formulation, which improves patient-care setting usability. This multi-arm, double-blinded, randomized trial enrolled 235 healthy men and women to receive either a refrigerated (RF) or frozen formulation (FF) of VGX-3100. Three doses were administered intramuscularly with electroporation at 0, 4, and 12 weeks. Non-inferiority of RF to FF was assessed by comparing the proportion of subjects who achieved a ≥2-fold increase from baseline to Week 14 in Spot Forming Units/106 PMBCs using an interferon-γ enzyme-linked immunospot assay. There were no related SAEs. Injection site reactions were the most common adverse event (54%, RF; 66%, FF) the majority of which resolved within a few minutes following administration. The primary endpoint was met with 89.9% of RF recipients and 97.2% of FF recipients reaching a ≥2-fold rise in SFU/106 PBMC, 2 weeks following the last dose; RF was statistically non-inferior to FF (p = .022). A systemic, immunologic approach has the potential to fill a critical gap in the ability to treat men and women with high grade HPV diseases. These safety and immunogenicity data are supportive of the continued development of a refrigerated formulation of VGX-3100.

Immune Therapy Targeting E6/E7 Oncogenes of Human Paillomavirus Type 6 (HPV-6) Reduces or Eliminates the Need for Surgical Intervention in the Treatment of HPV-6 Associated Recurrent Respiratory Papillomatosis.

: Background: Recurrent respiratory papillomatosis (RRP) is a rare disorder characterized by the generation of papillomas of the aerodigestive tract, usually associated with human papilloma virus (HPV) subtypes 6, 11. INO-3106 is a DNA plasmid-based immunotherapy targeting E6 and E7 proteins of HPV6, in order to create a robust immune T cell response. METHODS: Testing of INO-3016 in animal models confirmed immunogenicity of the DNA-based therapy. A single-site open-label Phase 1 study was initiated for patients with HPV6-positive RRP. Patients were dosed with INO-3106 with or without INO-9012, a DNA plasmid immunotherapy that encodes IL-12, delivered intramuscularly (IM) in combination with electroporation (EP) with the CELLECTRA® device. Patients received an escalating dose of INO-3106, 3 mg once and then 6 mg for three additional doses, each dose three weeks apart, with the third and fourth doses co-administered with INO-9012. The primary objective of the study was to evaluate the safety and tolerability of INO-3106 with and without INO-9012. The secondary objective was to determine cellular immune responses to INO-3106 with and without INO-9012. Exploratory objectives included preliminary clinical efficacy to the therapy. RESULTS: Three patients were enrolled in this study, of which two had RRP. Study therapy was well-tolerated, with no related serious adverse events and all related adverse events (AEs) were low-grade. Injection site pain was the most common related AE reported. Immunogenicity was evidenced by multiple immune assays showing engagement and expansion of an HPV6-specific cellular response, including cytotoxic T cells. Preliminary efficacy was demonstrated in patients with RRP in the form of reduction in need for surgical intervention for papilloma growth. Prior to intervention, both patients required surgical intervention approximately every 180 days. One patient demonstrated a greater than three-fold increase in surgery avoidance (584 days) and the other patient remains completely surgery-free as of the last contact at 915 days, a greater than 5-fold increase in surgery interval. CONCLUSION: INO-3106 with and without INO-9012 was well tolerated, immunogenic and demonstrated preliminary efficacy in patients with HPV6-associated RRP aerodigestive lesions. Further clinical study is indicated.

Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine.

BACKGROUND: Rotavirus is a leading cause of childhood gastroenteritis and death worldwide. METHODS: We studied healthy infants approximately 6 to 12 weeks old who were randomly assigned to receive three oral doses of live pentavalent human-bovine (WC3 strain) reassortant rotavirus vaccine containing human serotypes G1, G2, G3, G4, and P[8] or placebo at 4-to-10-week intervals in a blinded fashion. Active surveillance was used to identify subjects with serious adverse and other events. RESULTS: The 34,035 infants in the vaccine group and 34,003 in the placebo group were monitored for serious adverse events. Intussusception occurred in 12 vaccine recipients and 15 placebo recipients within one year after the first dose including six vaccine recipients and five placebo recipients within 42 days after any dose (relative risk, 1.6; 95 percent confidence interval, 0.4 to 6.4). The vaccine reduced hospitalizations and emergency department visits related to G1-G4 rotavirus gastroenteritis occurring 14 or more days after the third dose by 94.5 percent (95 percent confidence interval, 91.2 to 96.6 percent). In a nested substudy, efficacy against any G1-G4 rotavirus gastroenteritis through the first full rotavirus season after vaccination was 74.0 percent (95 percent confidence interval, 66.8 to 79.9 percent); efficacy against severe gastroenteritis was 98.0 percent (95 percent confidence interval, 88.3 to 100 percent). The vaccine reduced clinic visits for G1-G4 rotavirus gastroenteritis by 86.0 percent (95 percent confidence interval, 73.9 to 92.5 percent). CONCLUSIONS: This vaccine was efficacious in preventing rotavirus gastroenteritis, decreasing severe disease and health care contacts. The risk of intussusception was similar in vaccine and placebo recipients. (ClinicalTrials.gov number, NCT00090233.)

Immunotherapy Targeting HPV16/18 Generates Potent Immune Responses in HPV-Associated Head and Neck Cancer.

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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)/106 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%). CONCLUSIONS: 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.

Efficacy of pentavalent human-bovine (WC3) reassortant rotavirus vaccine based on breastfeeding frequency.

The efficacy of a live, oral, pentavalent rotavirus vaccine against G1-4 rotavirus gastroenteritis (RVGE) was retrospectively assessed based on breastfeeding frequency among 5098 infants in a placebo-controlled trial. The efficacy against any RVGE severity for infants never breastfed, sometimes breastfed, or exclusively breastfed was 68.3%, 82.2%, and 68.0%, respectively. The efficacy against severe RVGE was 100%, 95.4%, and 100%, respectively. Breastfeeding did not seem to adversely impact the efficacy of pentavalent rotavirus vaccine.

Accounting for interim safety monitoring of an adverse event upon termination of a clinical trial.

Upon termination of a clinical trial that uses interim evaluations to determine whether the trial can be stopped, a proper statistical analysis must account for the interim evaluations. For example, in a group-sequential design where the efficacy of a treatment regimen is evaluated at interim stages, and the opportunity to stop the trial based on positive efficacy findings exists, the terminal p-value, point estimate, and confidence limits of the outcome of interest must be adjusted to eliminate bias. While it is standard practice to adjust terminal statistical analyses due to opportunities to stop for "positive" findings, adjusting due to opportunities to stop for "negative" findings is also important. Stopping rules for negative findings are particularly useful when monitoring a specific rare serious adverse event in trials designed to show safety with respect to the event. In these settings, establishing conservative stopping rules are appropriate, and therefore accounting for the interim monitoring can have a substantial effect on the final results. Here I present a method to account for interim safety monitoring and illustrate its usefulness. The method is demonstrated to have advantages over methodology that does not account for interim monitoring.

Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine (PCV15) in healthy infants.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 and Immunologic Biomarkers for Histologic Regression of High-Grade Cervical Dysplasia and Clearance of HPV16 and HPV18 after Immunotherapy.

Purpose: As previously reported, treatment of high-grade cervical dysplasia with VGX-3100 resulted in complete histopathologic regression (CR) concomitant with elimination of HPV16/18 infection in 40.0% of VGX-3100-treated patients compared with only 14.3% in placebo recipients in a randomized phase IIb study. Here, we identify clinical and immunologic characteristics that either predicted or correlated with therapeutic benefit from VGX-3100 to identify parameters that might guide clinical decision-making for this disease.Experimental Design: We analyzed samples taken from cervical swabs, whole blood, and tissue biopsies/resections to determine correlates and predictors of treatment success.Results: At study entry, the presence of preexisting immunosuppressive factors such as FoxP3 and PD-L1 in cervical lesions showed no association with treatment outcome. The combination of HPV typing and cervical cytology following dosing was predictive for both histologic regression and elimination of detectable virus at the efficacy assessment 22 weeks later (negative predictive value 94%). Patients treated with VGX-3100 who had lesion regression had a statistically significant >2-fold increase in CD137+perforin+CD8+ T cells specific for the HPV genotype causing disease. Increases in cervical mucosal CD137+ and CD103+ infiltrates were observed only in treated patients. Perforin+ cell infiltrates were significantly increased >2-fold in cervical tissue only in treated patients who had histologic CR.Conclusions: Quantitative measures associated with an effector immune response to VGX-3100 antigens were associated with lesion regression. Consequently, these analyses indicate that certain immunologic responses associate with successful resolution of HPV-induced premalignancy, with particular emphasis on the upregulation of perforin in the immunotherapy-induced immune response. Clin Cancer Res; 24(2); 276-94. ©2017 AACR.

Concomitant use of an oral live pentavalent human-bovine reassortant rotavirus vaccine with licensed parenteral pediatric vaccines in the United States.

BACKGROUND: A live pentavalent rotavirus vaccine (PRV) containing 5 human-bovine (WC3) reassortants expressing human serotypes G1, G2, G3, G4 and P1A[8] was evaluated in a blinded, placebo-controlled study. Possible interactions between PRV and concomitantly administered licensed pediatric vaccines were investigated in a United States-based nested substudy (Concomitant Use Study) of the Rotavirus Efficacy and Safety Trial. METHODS: From 2002 to 2003, healthy infants approximately 6 to 12 weeks of age at entry were randomized to receive either 3 oral doses of PRV or placebo at 4- to 10-week intervals. Subjects were also to receive combined Haemophilus influenzae type b and hepatitis B vaccine (2 doses), diphtheria and tetanus toxoids and acellular pertussis vaccine (3 doses), inactivated poliovirus vaccine (2 doses) and pneumococcal conjugate vaccine (3 doses) on the same day; oral poliovirus vaccine was not administered. Immunogenicity was assessed by measuring antibody responses to PRV and antigens contained in the licensed vaccines. Cases of rotavirus gastroenteritis were defined by forceful vomiting and/or -3 watery or looser-than-normal stools within a 24-hour period, and detection of rotavirus antigen in the stool. Safety was assessed by reporting of adverse events using diary cards. RESULTS: The Concomitant Use Study enrolled 662 subjects in the PRV group and 696 subjects in the placebo group. For the 17 antigens in the concomitantly administered vaccines, antibody responses were similar in PRV and placebo recipients, except for moderately diminished antibody responses to the pertactin component of pertussis vaccine. Efficacy of PRV against rotavirus gastroenteritis of any severity was 89.5% (95% CI = 26.5-99.8%). PRV was generally well tolerated when given concomitantly with the prespecified vaccines. CONCLUSIONS: In this study, antibody responses to the concomitantly administered vaccines were generally similar in PRV and placebo recipients. PRV was efficacious and well tolerated when given concomitantly with pediatric vaccines licensed in the United States.

Safety and efficacy of the pentavalent human-bovine (WC3) reassortant rotavirus vaccine in healthy premature infants.

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 < or =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 > 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% CI: 82.2-100) 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.

The integrated phase III safety profile of the pentavalent human-bovine (WC3) reassortant rotavirus vaccine.

BACKGROUND: Rotavirus gastroenteritis is a significant cause of morbidity and mortality. OBJECTIVE: To perform an integrated safety analysis of data from the Phase III studies of the pentavalent rotavirus vaccine (PRV). METHODS: Healthy 6- to 12-week-old infants received 3 doses of PRV or placebo at 4- to 10-week intervals in 3 Phase III, blinded, randomized, placebo-controlled trials. Active surveillance for serious adverse events (AE), including intussusception, was performed at 7, 14, and 42 days after each dose. Other AEs occurring within 42 days after each dose were documented on Vaccination Report Cards. Fecal shedding of vaccine-virus strains was evaluated by plaque assay and electropherotyping. RESULTS: Intussusception and other serious AEs were evaluated among 71,799 vaccinated subjects. Within 42 days after any dose, intussusception occurred among 6 PRV and 5 placebo recipients. All AEs were evaluated among 11 722 vaccinated subjects. Within the week following the first dose, the incidences of fever and irritability were similar among PRV and placebo recipients, although diarrhea and vomiting occurred more frequently among PRV recipients versus placebo recipients (10.4% vs. 9.1% and 6.7% vs. 5.4%, respectively). Fecal shedding of vaccine-virus strains occurred in 8.9% of 360 PRV recipients after the first dose. CONCLUSIONS: Across the 3 Phase III clinical trials, PRV was well tolerated, with no increased clinical risk of intussusception. Fecal shedding of vaccine-virus strains occurred infrequently and in low amounts, suggesting the risk of transmission is unlikely.