Vaccine-related Adverse Events Research Articles

IMT-07 CLINICAL TRIAL OF A COCKTAIL WILMS’ TUMOR 1 (WT1) VACCINATION USING TWO HLA CLASS I PEPTIDES AND ONE CLASS II PEPTIDE FOR RECURRENT MALIGNANT GLIOMAS

PURPOSEOur clinical trials shows the safety and clinical efficacy of Wilms’ tumor 1 (WT1) human leukocyte antigen (HLA) class I (Izumoto S et al. J Neurosurg. 2008) and class II (Tsuboi A et al. Cancer Immunol Immunother. 2019) peptide vaccination for recurrent malignant gliomas have been established. We have developed a cocktail vaccine (WT1 trio) containing two class I peptides (HLA-A*24:02 and HLA-A*02:01) and one II class peptide to improve more effective immunological response and improve patient’s prognosis. Clinical trial of a cocktail vaccination using WT1 HLA class I and II peptides for recurrent malignant gliomas is planned to verify its safety, clinical efficacy and usefulness of surrogate markers.PATIENTS AND METHODSTwenty-three patients with recurrent malignant gliomas, which showed WT1-positive in tumor samples and HLA-A*24:02 or HLA-A*02:01-positive in blood sample, were enrolled. These patients (age: 26–72 years old, average: 49.4) included 15 cases of glioblastomas and 8 of anaplastic astrocytomas. Patients received a WT1 trio vaccine intradermally, 7 times at 2-week intervals during 3 months.WT1-DTH and WT1-IgG antibody were regularly measured. Vaccine-related adverse events, best clinical response and the transfer rate of long-term administration of WT1 trio vaccination were estimated.RESULTSWT1-DTH positive cases were 12, WT1-IgG antibody positive were in 11. In most patients, WT1 -DTH positiveness coincided with that of WT1-IgG antibody. 9 of 11 cases showed stable disease at 3 months and transferred long-term administration of WT1 trio vaccination. Transfer rate in GBM and AA of long-term administration was 33% and 25%, respectively. Grade1 skin eruption was observed at the injection sites in 15 cases, but no significant adverse events related with vaccination were shown.CONCLUSIONthe safety and clinical efficacy of WT1 trio vaccination was verified for recurrent malignant gliomas. WT1-DTH and WT1-IgG antibody may be useful surrogate markers.

Postexposure Prophylaxis With rVSV-ZEBOV Following Exposure to a Patient With Ebola Virus Disease Relapse in the United Kingdom: An Operational, Safety, and Immunogenicity Report.

BackgroundIn October 2015, 65 people came into direct contact with a healthcare worker presenting with a late reactivation of Ebola virus disease (EVD) in the United Kingdom. Vaccination was offered to 45 individuals with an initial assessment of high exposure risk.MethodsApproval for rapid expanded access to the recombinant vesicular stomatitis virus–Zaire Ebola virus (rVSV-ZEBOV) vaccine as an unlicensed emergency medicine was obtained from the relevant authorities. An observational follow-up study was carried out for 1 year following vaccination.ResultsTwenty-six of 45 individuals elected to receive vaccination between 10 and 11 October 2015 following written informed consent. By day 14, 39% had seroconverted, increasing to 87% by day 28 and 100% by 3 months, although these responses were not always sustained. Neutralizing antibody responses were detectable in 36% by day 14 and 73% at 12 months. Common side effects included fatigue, myalgia, headache, arthralgia, and fever. These were positively associated with glycoprotein-specific T-cell but not immunoglobulin (Ig) M or IgG antibody responses. No severe vaccine-related adverse events were reported. No one exposed to the virus became infected.ConclusionsThis paper reports the use of the rVSV-ZEBOV vaccine given as an emergency intervention to individuals exposed to a patient presenting with a late reactivation of EVD. The vaccine was relatively well tolerated, but a high percentage developed a fever ≥37.5°C, necessitating urgent screening for Ebola virus, and a small number developed persistent arthralgia.

A phase I trial evaluating the safety and immunogenicity of a candidate tuberculosis vaccination regimen, ChAdOx1 85A prime – MVA85A boost in healthy UK adults

BackgroundThis phase I trial evaluated the safety and immunogenicity of a candidate tuberculosis vaccination regimen, ChAdOx1 85A prime-MVA85A boost, previously demonstrated to be protective in animal studies, in healthy UK adults. MethodsWe enrolled 42 healthy, BCG-vaccinated adults into 4 groups: low dose Starter Group (n = 6; ChAdOx1 85A alone), high dose groups; Group A (n = 12; ChAdOx1 85A), Group B (n = 12; ChAdOx1 85A prime – MVA85A boost) or Group C (n = 12; ChAdOx1 85A – ChAdOx1 85A prime – MVA85A boost). Safety was determined by collection of solicited and unsolicited vaccine-related adverse events (AEs). Immunogenicity was measured by antigen-specific ex-vivo IFN-γ ELISpot, IgG serum ELISA, and antigen-specific intracellular IFN-γ, TNF-α, IL-2 and IL-17. ResultsAEs were mostly mild/moderate, with no Serious Adverse Events. ChAdOx1 85A induced Ag85A-specific ELISpot and intracellular cytokine CD4+ and CD8+ T cell responses, which were not boosted by a second dose, but were boosted with MVA85A. Polyfunctional CD4+ T cells (IFN-γ, TNF-α and IL-2) and IFN-γ+, TNF-α+ CD8+ T cells were induced by ChAdOx1 85A and boosted by MVA85A. ChAdOx1 85A induced serum Ag85A IgG responses which were boosted by MVA85A. ConclusionA ChAdOx1 85A prime – MVA85A boost is well tolerated and immunogenic in healthy UK adults.

Cold chain transportation decision in the vaccine supply chain

Vaccines are a special kind of drug, the quality of which is highly sensitive to temperature and directly related to public health. Recently, numerous vaccine-related adverse events have occurred in the world, especially in developing countries, due to vaccines being exposed to inappropriate temperatures during their transportation. This paper considers the vaccine supply chain including a distributor and a retailer (hospital or clinic). The distributor decides to use a cold chain or non-cold chain to transport the vaccines. The retailer performs an inspection when receiving the vaccines. First, a basic model is developed to study the conditions under which the distributor will transport the vaccines via a cold chain or non-cold chain. Then, two common inspection policies (a single-step one and a two-step one) are introduced into the basic model to explore the impact of the retailer's inspection at the end of transportation on the distributor's original decision. We show that the retailer's single-step inspection influences the distributor to choose the cold chain option. Interestingly, we prove that the two-step inspection policy is less effective than the single-step one in this effect. We suggest that the retailer's role in improving the distributor's non-cold chain transportation behavior should be fully used.

LB10. A Randomized, Double-Blind, Placebo-Controlled Efficacy Trial of a Vaccine to Prevent Chronic Hepatitis C Virus Infection in an at-Risk Population

BackgroundThe development of a safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of elimination efforts, providing the rationale for the first HCV vaccine efficacy trial.MethodsIn a randomized, multicenter, double-blind, placebo-controlled efficacy trial (NCT01436357), we evaluated a recombinant chimpanzee adenovirus 3 vector vaccine prime followed by a recombinant modified vaccinia Ankara boost, both encoding nonstructural proteins of HCV. HCV-uninfected adults 18–45 years old at-risk for HCV infection due to injection drug use were randomized to receive the prime-boost regimen or placebo at Days 0 and 56. Trial participants were monitored for vaccine reactogenicity, adverse events, and HCV viremia. Vaccine safety, immunogenicity, and efficacy against progression to chronic HCV infection were assessed.ResultsA total of 455 subjects received the prime-boost regimen or two doses of placebo, with 202 and 199 in the respective groups included in the according-to-protocol efficacy cohort. Overall incidence of infection was 14.1 infections per 100 person-years. There were no differences in development of chronic infection between vaccine and placebo arms, with 14 chronically infected subjects in each group. Specifically, the vaccine efficacy in preventing chronic infection was −0.53 (95% confidence interval [CI], −2.5 to 0.34). Of vaccinated subjects, 78% generated T-cell responses to ≥1 vaccine-encoded HCV antigens. The vaccine was generally safe and well tolerated with no serious vaccine-related adverse events. There were more solicited reports of adverse events after either injection in the vaccine group (81%) than in the placebo group (59%), with the difference mainly due to injection-site reactions. Serious adverse events and deaths occurred with similar frequencies in the two groups.ConclusionA randomized, placebo controlled, Phase I/II trial of a prime-boost vaccine to prevent chronic HCV infection was completed in an at-risk population, demonstrating the feasibility of conducting rigorous vaccine research in people who inject drugs. The regimen elicited robust immune responses without evident safety concerns, but did not provide protection against chronic HCV infection.DisclosuresVentzislav Vassilev, PhD, GlaxoSmithKlein Vaccines (Employee), Lan Lin, MD, GlaxoSmithKlein Vaccines (Employee), Alfredo Nicosia, PhD, ReiThera (Employee, Shareholder), Antonella Folgori, PhD, ReiThera (Employee), ReiThera (Employee, Shareholder. Other Authors: No reported disclosures.

Immunogenicity and safety of a quadrivalent inactivated influenza vaccine in pregnant women: a randomized, observer-blind trial

ABSTRACT Vaccination against influenza during pregnancy provides direct protection to pregnant women and indirect protection to their infants. Trivalent inactivated influenza vaccines (IIV3s) are safe and effective during pregnancy, but quadrivalent inactivated influenza vaccines (IIV4s) have not been evaluated in pregnant women and their infants. Here, we report the results of a randomized phase IV study to evaluate the immunogenicity and safety of IIV4 vs. IIV3 in pregnant women. Participants aged ≥18 years at weeks 20 to 32 of gestation were randomly assigned in a 2:1 ratio to receive a single dose of IIV4 (n = 230) or IIV3 (n = 116). Between baseline and 21 days after vaccination, hemagglutination inhibition (HAI) antibody titers increased in both groups by similar magnitudes for the two influenza A strains and single B strain common to IIV4 and IIV3. For the additional B strain in IIV4, HAI titers were higher in IIV4 recipients than IIV3 recipients (post-/pre-vaccination geometric mean titer ratio, 6.3 [95% CI: 5.1 − 7.7] vs. 3.4 [95% CI: 2.7 − 4.3]). At delivery, in both groups, HAI antibody titers for all strains were 1.5 − 1.9-fold higher in umbilical cord blood than in maternal blood, confirming active transplacental antibody transfer. Rates of solicited and unsolicited vaccine-related adverse events in mothers were similar between the two groups. Live births were reported for all participants and there were no vaccine-related adverse events in newborns. These results suggest IIV4 is as safe and immunogenic as IIV3 in pregnant women, and that maternal immunization with IIV4 should protect newborns against influenza via passively acquired antibodies.

Diffuse uveitis and chorioretinal changes after yellow fever vaccination: a re-emerging epidemic

BackgroundWith increasing incidence of yellow fever, mass campaign vaccinations are underway and little ophthalmological alterations have been reported in literature, specially regarding non-combined vaccines.Case presentationWe report the case of a patient with no previous ocular or systemic diseases whom received a single dose of yellow fever vaccination and developed haematological, hepatic and renal alterations progressing with a later onset bilateral asymmetric diffuse uveitis. Ophthalmological findings included fine keratic precipitates scattered throughout the cornea and mild vitritis. Multimodal evaluation showed subtle puntiform choriocapillaris changes with decreased vascular density associated. The patient had a good visual outcome after mild oral prednisone dose, but the image findings have not presented remission.ConclusionsClinicians should be aware of clinical and subclinical ocular manifestations such as subtle puntiform choriocapillaris changes as possible vaccine-related adverse events with potential to impact vision.

Factors associated with influenza vaccination in Japanese elderly outpatients

Elderly patients benefit from influenza vaccination, but the number of Japanese elderly patients who are vaccinated is insufficient. Several factors are associated with influenza vaccination acceptance, but little is known about Japanese elderly outpatients. The purpose of this study was to examine factors associated with influenza vaccination in elderly outpatients in Japan. During the 2017-2018 influenza season, outpatients from one hospital and one clinic in Kitaibaraki City, Ibaraki, Japan, participated in this study. Patients answered a self-report questionnaire exploring factors such as their vaccination status during the 2017-2018 season, past influenza vaccination, perceived susceptibility to influenza and adverse events of the vaccine, perceived vaccine efficacy, physician recommendations. Multivariable logistic regression analyses were conducted to identify factors associated with vaccination. Of 377 patients, 316 (83.8%) responded, and the vaccination rate was 57%. Eighty-three patients (27.0%) reported that their physician recommended the influenza vaccine. In multivariate analysis, influenza vaccination was associated with higher age (odds ratio (OR) 1.09, 95% confidence interval (CI) 1.03-1.14), physician recommendations (OR 2.49, 95% CI 1.18-5.25), low perceived susceptibility to vaccine-related adverse events (OR 0.33, 95% CI 0.15-0.74), and belief in vaccine efficacy (OR 4.73, 95% CI 2.08-10.8). Influenza vaccination was associated with belief in vaccine efficacy, perceived susceptibility to vaccine-related adverse events, physician recommendations, and older age. Increasing the frequency of physician recommendations may lead to increased vaccination coverage.

Long-term incidence of severe malaria following RTS,S/AS01 vaccination in children and infants in Africa: an open-label 3-year extension study of a phase 3 randomised controlled trial

Results from a previous phase 3 study showed efficacy of the RTS,S/AS01 vaccine against severe and clinical malaria in children (in 11 sites in Africa) during a 3-4-year follow-up. We aimed to investigate malaria incidence up to 7 years postvaccination in three of the sites of the initial study. In the initial phase 3 study, infants aged 6-12 weeks and children aged 5-17 months were randomly assigned (1:1:1) to receive four RTS,S/AS01 doses (four-dose group), three RTS,S/AS01 doses and a comparator dose (three-dose group), or four comparator doses (control group). In this open-label extension study in Korogwe (Tanzania), Kombewa (Kenya), and Nanoro (Burkina Faso), we assessed severe malaria incidences as the primary outcome for 3 additional years (January, 2014, to December, 2016), up to 6 years (younger children) or 7 years (older children) postprimary vaccination in the modified intention-to-treat population (ie, participants who received at least one dose of the study vaccine). As secondary outcomes, we evaluated clinical malaria incidences and serious adverse events. This trial is registered with ClinicalTrials.gov, number NCT02207816. We enrolled 1739 older children (aged 5-7 years) and 1345 younger children (aged 3-5 years). During the 3-year extension, 66 severe malaria cases were reported, resulting in severe malaria incidence of 0·004 cases per person-years at risk (PPY; 95% CI 0-0·033) in the four-dose group, 0·007 PPY (0·001-0·052) in the three-dose group, and 0·009 PPY (0·001-0·066) in the control group in the older children category and a vaccine efficacy against severe malaria that did not contribute significantly to the overall efficacy (four-dose group 53·7% [95% CI -13·7 to 81·1], p=0·093; three-dose group 23·3% [-67·1 to 64·8], p=0·50). In younger children, severe malaria incidences were 0·007 PPY (0·001-0·058) in the four-dose group, 0·007 PPY (0·001-0·054) in the three-dose group, and 0·011 PPY (0·001-0·083) in the control group. Vaccine efficacy against severe malaria also did not contribute significantly to the overall efficacy (four-dose group 32·1% [-53·1 to 69·9], p=0·35; three-dose group 37·6% [-44·4 to 73·0], p=0·27). Malaria transmission was still occurring as evidenced by an incidence of clinical malaria ranging from 0·165 PPY to 3·124 PPY across all study groups and sites. In older children, clinical malaria incidence was 1·079 PPY (95% CI 0·152-7·662) in the four-dose group, 1·108 PPY (0·156-7·868) in the three-dose group, and 1·016 PPY (0·14-7·213) in the control group. In younger children, malaria incidence was 1·632 PPY (0·23-11·59), 1·563 PPY (0·22-11·104), and 1·686 PPY (0·237-11·974), respectively. In the older age category in Nanoro, clinical malaria incidence was higher in the four-dose (2·444 PPY; p=0·011) and three-dose (2·411 PPY; p=0·034) groups compared with the control group (1·998 PPY). Three cerebral malaria episodes and five meningitis cases, but no vaccine-related severe adverse events, were reported. Overall, severe malaria incidence was low in all groups, with no evidence of rebound in RTS,S/AS01 recipients, despite an increased incidence of clinical malaria in older children who received RTS,S/AS01 compared with the comparator group in Nanoro. No safety signal was identified. GlaxoSmithKline Biologicals SA.

Abstract CT038: Results of a Phase Ib trial of an autologous cell vaccine for newly diagnosed glioblastoma

Abstract Background: We evaluated an autologous cell vaccine, a combination of GBM tumor cells and an antisense molecule against insulin-like growth factor type 1 receptor DNA/mRNA (IGF-1R AS ODN), in adults with newly diagnosed GBM (NCT02507583). Methods: Tumor cells collected during resection were treated ex vivo with IGF-1R AS ODN, encapsulated in biodiffusion chambers with IGF-1R AS ODN, irradiated, then implanted in an abdominal acceptor site on the first post-operative day. Four vaccine exposures were evaluated: lowest (10 chambers implanted for 24 hours); lower (10 / 48 hours); higher (20 / 24 hours); and highest (20 / 48 hours). Standard of care (SOC; ie, radiotherapy and temozolomide) was initiated after 4-6 weeks. Randomization was halted after patient 23 and subsequent patients received the highest exposure. Evaluation of safety and tumor responses were the primary and secondary objectives, respectively. Exploratory objectives included assessment of progression-free survival (PFS) and overall survival (OS). The SOC comparator group was an antecedent cohort of 35 newly diagnosed, GBM patients treated at the same center. Results: Thirty-three patients were enrolled between September 1, 2015 and March 1, 2018. Six, 5, 5, and 17 patients received the lowest, lower, higher, and highest exposures. Median (range) follow-up was 13 (4-39) months. As of the January 1, 2019 cutoff, no vaccine-related adverse events were observed. Seventeen of 33 (51.5%) remained progression-free, 12 of whom are alive and functioning well. The autologous cell vaccine significantly prolonged PFS and OS vs. SOC (Table). Survival advantages were conferred by the highest exposure to the autologous cell vaccine and good T cell function prior to surgery. Conclusions: This vaccine was well-tolerated and prolonged PFS and OS when compared with SOC alone. Table.Survival outcomes in patients receiving vaccine vs. SOC aloneTreatment group2 yr OS estimateMedian OS (mo)p-value v. SOC for OS1 yr PFS estimateMedian PFS estimatep-value v. SOC for PFSVaccine highest dose (N=17)34%21.9.04141%10.4.031Vaccine all (ITT, N=33)31%17.3.01642%9.8.018SOC (n=35)14%12.128%6.9 Citation Format: David W. Andrews, Samantha Garcia, Kevin D. Judy, Larry A. Harshyne, Sanjana Govindarajan, Lawrence Kenyon, Kiran Talekar, Adam Flanders, Kofi-Buaku Atsina, Lyndon Kim, Nina L. Martinez, Wenyin Shi, Maria Werner-Wasik, Mikhail Prosniak, Mark T. Curtis, Rhonda Kean, Emily Bongiorno, Sami Sauma, Kara Pigott, Charles B. Scott, D Craig Hooper. Results of a Phase Ib trial of an autologous cell vaccine for newly diagnosed glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT038.

Immunogenicity and safety of a novel recombinant protective antigen anthrax vaccine (GC1109), a randomized, single-blind, placebo controlled phase II clinical study

BackgroundThe demand on effective and safe anthrax vaccine is increasing as a part of the preparedness for possible bioterrorism in the future. We performed a randomized, single-blind, placebo controlled phase II clinical study to evaluate the immunogenicity and safety of a novel recombinant protective antigen (rPA) anthrax vaccine, GC1109, in healthy adult volunteers. MethodsParticipants were randomized to experiment groups (0.3 mL, 0.5 mL, and 1.0 mL of GC1109) or placebo group (normal saline 0.5 mL) in 2:2:2:1 ratio. They received respective vaccines intramuscularly at 0, 4 and 8 weeks. Immunogenicity was evaluated by seroconversion rate and geometric mean titer (GMT) of lethal toxin neutralizing assay (TNA) and anti-PA IgG by ELISA. Safety was assessed by laboratory tests, and solicited and unsolicited adverse events on diary cards. Results30, 29, 30 participants were randomized to 0.3, 0.5, and 1.0 mL of GC1109 groups, respectively, while 15 to placebo group. 92 participants received all three doses. In per-protocol analysis, TNA GMTs at week 12 were 296.5, 285.2, and 433.2 in the three groups, respectively. Seroconversion rates measured by ELISA were 100% at week 12 in the three groups. Local and systemic vaccine-related adverse events were frequent; however, most of them were mild, and no serious events were observed. ConclusionsA new rPA anthrax vaccine GC1109 was immunogenic after three doses of intramuscular administration, and was well-tolerated.

The use of natural language processing to identify Tdap-related local reactions at five health care systems in the Vaccine Safety Datalink

ObjectiveLocal reactions are the most common vaccine-related adverse event. There is no specific diagnosis code for local reaction due to vaccination. Previous vaccine safety studies used non-specific diagnosis codes to identify potential local reaction cases and confirmed the cases through manual chart review. In this study, a natural language processing (NLP) algorithm was developed to identify local reaction associated with tetanus-diphtheria-acellular pertussis (Tdap) vaccine in the Vaccine Safety Datalink. MethodsPresumptive cases of local reactions were identified among members ≥ 11 years of age using ICD-9-CM codes in all care settings in the 1–6 days following a Tdap vaccination between 2012 and 2014. The clinical notes were searched for signs and symptoms consistent with local reaction. Information on the timing and the location of a sign or symptom was also extracted to help determine whether or not the sign or symptom was vaccine related. Reactions triggered by causes other than Tdap vaccination were excluded. The NLP algorithm was developed at the lead study site and validated on a stratified random sample of 500 patients from five institutions. ResultsThe NLP algorithm achieved an overall weighted sensitivity of 87.9%, specificity of 92.8%, positive predictive value of 82.7%, and negative predictive value of 95.1%. In addition, using data at one site, the NLP algorithm identified 3326 potential Tdap-related local reactions that were not identified through diagnosis codes. ConclusionThe NLP algorithm achieved high accuracy, and demonstrated the potential of NLP to reduce the efforts of manual chart review in vaccine safety studies.

Immunogenicity and safety of a trivalent inactivated influenza vaccine produced in Shenzhen, China versus a comparator influenza vaccine: a phase IV randomized study

ABSTRACTSeasonal influenza causes substantial morbidity and mortality in China, which largely results from limited vaccine accessibility and poor vaccination coverage. Since 2013, Sanofi Pasteur’s facilities in Shenzhen, China have produced a trivalent inactivated influenza vaccine (Shz-IIV3) for each influenza season according to Chinese pharmacopeia requirements. However, the immunogenicity of Shz-IIV3 has not been compared to existing Chinese trivalent inactivated influenza vaccines (IIV3s). Here, we describe the results of a phase IV, observer-blind, randomized study to evaluate whether the immunogenicity of Shz-IIV3 was non-inferior to a comparator IIV3 (Hualan Biological Engineering Inc) also manufactured and licensed in China. Healthy adults aged 18−59 years were randomly assigned in a 1:1 ratio to receive a single 0.5-mL intramuscular injection of the 2017–2018 Northern Hemisphere formulation of Shz-IIV3 (n = 800) or the comparator IIV3 (n = 799). Between baseline and day 28 after vaccination, hemagglutination inhibition titers for the three vaccine strains increased by at least 4-fold and were of similar magnitude in Shz-IIV3 and comparator IIV3 recipients. The rate of seroconversion or significant increase in titers was 62% to 92% in Shz-IIV3 recipients, and 63% to 91% in comparator IIV3 recipients. Post-vaccination hemagglutination inhibition titers and seroconversion rates for Shz-IIV3 were statistically non-inferior to the comparator IIV3 for all three influenza vaccine strains. Rates of solicited and unsolicited vaccine-related adverse events were similar between the two vaccine groups. These results demonstrated that Shz-IIV3 was as immunogenic and safe in adults as a comparator Chinese IIV3, and support the continued use of Shz-IIV3 in China.

Immunogenicity and safety of an intramuscular split-virion quadrivalent inactivated influenza vaccine in individuals aged ≥ 6 months in India

ABSTRACT A quadrivalent split-virion inactivated influenza vaccine (IIV4; Fluzone® Quadrivalent, Sanofi Pasteur) has been available in the US since 2013 for individuals aged ≥ 6 months. Here, we describe the results of an open-label, multicenter trial (WHO Universal Trial Number U1111-1143–8370) evaluating the immunogenicity and safety of IIV4 in Indian children aged 6–35 months and 3–8 years, adolescents aged 9–17 years, and adults aged ≥ 18 years (n = 100 per group). Post-vaccination hemagglutination inhibition titers for all strains in all age groups were ≥ 8 fold higher than at baseline (range, 8–51). At least 70% of participants in all age groups seroconverted or had a significant increase in titer for each strain. The most common solicited reactions were injection-site pain and tenderness, plus fever in participants 6–23 months and myalgia in older children and adolescents. All injection-site reactions and most systemic reactions were grade 1 or 2 and resolved within 3 days. Only three vaccine-related unsolicited adverse events were reported, all of which were grade 1 or 2 and transient. No immediate adverse events, adverse events leading to study discontinuation, adverse events of special interest, or serious adverse events were reported. This study showed that IIV4 was well tolerated and highly immunogenic in all age groups. This adds important data on the safety, tolerability, and immunogenicity of influenza vaccines in India.

Immunogenicity and Safety of Influenza Vaccination in Cancer Patients Receiving Immune Checkpoint Inhibitor

Background: Immune checkpoint inhibitors (ICIs) were recently introduced into routine clinical practice, but the immunogenicity and safety of influenza vaccination in cancer patients receiving ICIs have not been elucidated. We explored immunogenicity and safety in cancer patients receiving ICIs compared to cancer patients receiving cytotoxic chemotherapy. Methods: Adult cancer patients receiving ICIs or cytotoxic agents were prospectively enrolled in a 1:2 ratio. They received an intramuscular seasonal quadrivalent influenza vaccine on day 1 of the chemotherapeutic cycle. The serum hemagglutination inhibition (HAI) antibody titers were examined before and 4 weeks after vaccination. The primary endpoint was seroprotection rate and secondary endpoints were seroconversion rate and geometric mean antibody titer. Immune-related adverse events (irAEs) were screened by pre-defined measures. Findings: Among 154 eligible patients, 46 and 90 patients in the ICI and cytotoxic chemotherapy groups, respectively, were finally examined for HAI antibody titers. Seroprotection rates were higher in the ICI group than in the cytotoxic chemotherapy group (H1N1, 76% vs. 68%, P=0.111; H3N2, 89% vs. 70%, P=0.005; B-Yamagata, 83% vs. 54%, P=0.002; B-Victoria, 85% vs. 48%, P<0.001) and seroconversion rates were also higher in the ICI group (H1N1, 57% vs. 39%, P=0.086; H3N2, 52% vs. 27%, P=0.006; B-Yamagata, 54% vs. 30%, P=0.007; B-Victoria, 65% vs. 28%, P<0.001). The frequency of vaccine-related adverse events was comparable between the two groups. Only 4 (8.5%) irAEs occurred during the study period, which were all grade 1. Interpretation: Cancer patients receiving ICIs reach higher levels of influenza immunity by vaccination than those receiving cytotoxic chemotherapy, without increased frequency or severity of irAEs. Annual influenza vaccination should be encouraged in cancer patients receiving ICIs. Trial Registration Number: The study was registered at ClinicalTrials.gov (identifier NCT03590808). Funding Statement: GC Pharma (Yongin, Republic of Korea) and Seoul National University Hospital Research Fund (Seoul, Republic of Korea; No.04-2018-0520). Declaration of Interests: BK reports grants and personal fees from AstraZeneca, grants and personal fees from MSD, grants from ONO Pharmaceutical, personal fees from Genexine, outside the submitted work. S-AI reports grants and personal fees from AstraZeneca, grants and personal fees from Pfizer, personal fees from Amgen, personal fees from Eisai, personal fees from Hanmi Corp., personal fees from Novartis, personal fees from Roche, outside the submitted work. WBP reports grants from GC Pharma, grants from Seoul National University Hospital Research Fund, during the conduct of the study. All other authors declare no competing interests. Seoul National University Hospital reports grants from Alpha Biopharma, grants from AstraZeneca/MedImmune, grants from Hanmi Corp., grants from Janssen, grants from Merus, grants from Mirati Therapeutics, grants from MSD, grants from Novartis, grants from ONO Pharmaceutical, grants from Pfizer, grants from Roche/Genentech, grants from Takeda, grants from TP Therapeutics, grants from Xcovery, grants from Yuhan, outside the submitted work. Ethics Approval Statement: Written informed consents were obtained from all participants prior to vaccination. The study was approved by the Institutional Review Board of Seoul National University Hospital (IRB approval No. H-1806-088-951) and Seoul National University Bundang Hospital (IRB approval No. B-1808/484- 402).

A phase II, multicenter, single-arm trial of CV301 plus atezolizumab (Atezo) in locally advanced (unresectable) or metastatic urothelial cancer (UC).

TPS494 Background: Anti-PD1/PD-L1 can achieve durable responses in advanced UC but most patients (pts) do not respond. Combination strategies with agents that “prime” the immune system may improve outcomes. CV301 comprises two recombinant poxviruses, Modified Vaccinia Ankara (MVA) and Fowlpox (FPV), encoding the human transgenes for CEA, MUC-1, and a Triad of Co-stimulatory Molecules (TRICOM: ICAM-1, LFA-3, and B7-1). MVA-CV301 is used for priming doses and FPV-CV301 is used for booster doses to achieve a heterologous prime boost regimen. In preclinical studies, BN-platform vaccine plus PD1/PD-L1 inhibitors exhibited synergistic anti-tumor efficacy, T-cell infiltration, and PD-L1 upregulation in tumors. CEA and MUC-1 are expressed, in 41-90% and 55-91% of any stage UC, respectively, and in ~100% of metastatic UC. An ongoing Phase Ib trial of CV301 plus anti-PD-1 agent has demonstrated a similar safety profile to anti-PD-1 monotherapy with only mild vaccine-related adverse events (AEs). Methods: This is a Phase 2, single-arm, multi-institutional trial designed to study CV301 plus atezo as 1st-line treatment in pts with advanced UC ineligible for cisplatin-based chemotherapy regardless of PD-L1 (Cohort 1) and as salvage treatment in pts with UC progressing after platinum-based chemotherapy (Cohort 2). MVA-CV301 is given subcutaneously (SC) on Days 1 and 22 and FPV-CV301 SC every 21 days for 4 doses, then every 6 weeks until 6 months, then every 12 weeks until 2 years. Atezo 1200mg is given every 21 days. Primary endpoint is objective response rate (ORR; RECIST 1.1). Secondary endpoints: immune response, OS, PFS, response duration, AEs. Tumor and serial blood samples will be collected for biomarker analyses; 1-sided α is 0.025/cohort in this design. With a 2-stage design, success criteria are based on historic ORR (H0) and alternative ORR (H1) with ≥70% power. For Cohort 1, assuming H0 = 0.23, H1 = 0.43, then Cohort 1 sample size N1= 14, responders required at stage 1 to continue R1≥3, total accrual goal N = 33, total responders to reject H0, R≥13. For Cohort 2, assuming H0 = 0.15, H1 = 0.33, then N1= 13, R1≥2, N = 35, R≥10. Accrual has begun; completion is expected within 1 year. Clinical trial information: NCT03628716.

Safety of live attenuated varicella-zoster vaccine in patients with underlying illnesses compared with healthy adults: a prospective cohort study

BackgroundIn Japan, freeze-dried live attenuated varicella-zoster vaccine is available for adults aged ≥50 years to prevent herpes zoster. However, limited evidence has been accumulated regarding vaccine safety for patients with underlying illnesses, who have been considered as the high-risk group for herpes zoster.MethodsA prospective cohort study of 1200 healthy adults and 300 patients with underlying illnesses such as malignancy, diabetes mellitus, autoimmune diseases, and renal diseases was conducted. All subjects were vaccinated and then their adverse events (AEs) were followed for 28 days after vaccination. Key safety measures included any AEs, severe AEs (SAEs), and vaccine-related AEs such as injection-site AEs and systemic AEs. The frequencies and 95% confidence intervals of AEs were calculated.ResultsDuring the follow-up period, 2 SAEs (bone fracture and acute cholecystitis) among healthy adults and 1 SAE (disseminated mycobacteriosis) among patients with underlying illnesses were reported, although none of them was diagnosed as vaccine-related. Vaccine-related AEs were reported in 42% of healthy adults and patients with underlying illnesses, and the proportions were similar between the groups. The most frequent AEs were injection-site AEs in both groups (i.e., 41 and 39%), and systemic AEs were observed in 4% of both groups. Only among healthy adults, those with a history of herpes zoster were more likely to report injection-site AEs than those without a history of herpes zoster (53% vs 39%).ConclusionsThe present study confirmed the safety of freeze-dried, live attenuated varicella-zoster vaccine even in patients with underlying illnesses. A history of herpes zoster might be related to development of injection-site AEs in healthy adults.Trial registrationThe study was prospectively registered on Japic-Clinical Trials Information as JapicCTI-163415 on October 31, 2016.

Cost calculator for mass vaccination response to a US college campus outbreak of serogroup B meningococcal disease

ABSTRACT Serogroup B (MenB) is the leading cause of meningococcal disease among 16- to 23-year-olds in the United States and has been responsible for all 10 college outbreaks between 2011 and 2017. Outbreak-associated costs levy a substantial and unforeseen burden on colleges/universities and surrounding communities, in part because they involve collaboration with local and state health departments to develop points-of-dispensing (PODs) outbreak response plans and rapid mass vaccination of a large at-risk student population. The MenB outbreak at Providence College in 2015 was used as a case study to develop an Excel-based Meningococcal Outbreak Cost Calculator that uses target populations for mass vaccination to estimate the costs and resources associated with a meningococcal disease outbreak response. Resources include labor, medical supply, and other nonlabor costs (eg, vaccine-related adverse event costs) over an 18-month period following the outbreak declaration. Based on the actual Providence College population partially or fully vaccinated with MenB-FHbp (Trumenba®, Bivalent rLP2086) (3-dose schedule), the calculator estimated aggregate direct costs of $1,350,963 over 18 months post-outbreak for 4,418 individuals. For planned full vaccination of the enrolled undergraduate population (4,795 individuals), the tool estimated total costs of $1,798,399. In both cases, the majority of costs were for medical supplies (88%–89%) and contract services (7%–9%). This calculator can help to plan a mass vaccination campaign for MenB outbreak control, and underscores the need to vaccinate pre-emptively against diverse disease-causing strains before an outbreak occurs.

A Cuban Perspective on the Antivaccination Movement.

Vaccination is one of the most cost-effective interventions for control of communicable diseases. This health achievement could flounder if measures are not taken by health systems to prioritize immunization, increase vaccination rates and educate health professionals to address public concerns about vaccine safety and efficacy. Parents' refusal to vaccinate their children directly affects public health, because it puts both individual and group immunity in danger; immunization coverage is effective only when high population coverage is attained. The growing number of antivaccination (antivaxxer) groups around the world is alarming, contributing to falling vaccination rates. Troubling consequences include disease outbreaks in several countries globally and in our hemisphere. This article looks at the history and features of antivaxxer movements around the world and proposes ways the Cuban health system, through its National Immunization Program, can address dangers for the population associated with potentially negative infiuences of social-network antivaxxer campaigns. The paper underscores the role of mass and social media, health professional training and sustained competence, and the importance of a vaccine-related adverse events surveillance system. KEYWORDS Vaccination, immunization, antivaccination move-ment, antivaccine groups, primary health care, society, communi-cations media, social media, Cuba.

Immunogenicity and safety of double versus standard dose of the seasonal influenza vaccine in solid-organ transplant recipients: A randomized controlled trial

BackgroundThe use of vaccines with higher doses of antigen is an attractive strategy to improve the immunogenicity of influenza vaccination in transplant recipients. However, the effect of vaccination with a double-dose (DD) containing 30 µg of antigen in this population remains unknown. MethodsWe performed a randomized controlled trial to compare the immunogenicity and safety of DD (30 µg) vs. standard dose (SD, 15 µg) of a trivalent inactivated influenza vaccine in kidney and liver transplant recipients. Immunogenicity was assessed by hemagglutination-inhibition assay. Vaccine response was defined as seroconversion to at least one viral strain 2 weeks after vaccination and seroprotection as a titer ≥40. ResultsSixty-three kidney and 16 liver transplant recipients were enrolled. Forty patients received the DD and 39 the SD vaccine. Overall, 40% of patients in the DD compared to 26% in the SD group (P = 0.174) responded to vaccine. In the DD arm, more patients were seroprotected to all viral strains after vaccination (88% vs 69%, P = 0.048). Post vaccination geometric mean titers of antibodies were 131.9 vs. 89.7 (P = 0.187) for H1N1, 185.4 vs. 138.7 (P = 0.182) for H3N2, and 96.6 vs. 68.8 (P = 0.081) for influenza B with the DD vs. SD. In both groups, most of the adverse events were mild and no vaccine-related severe adverse events were observed. ConclusionDouble-dose influenza vaccine is safe and may increase antibody response in transplant recipients. In this population, DD vaccination could be an alternative when high-dose vaccine is not available. NCT02746783.