Immunogenicity Trial Research Articles

A phase 3 trial of safety, tolerability, and immunogenicity of V114, 15-valent pneumococcal conjugate vaccine, compared with 13-valent pneumococcal conjugate vaccine in adults 50 years of age and older (PNEU-AGE)

BackgroundPneumococcal conjugate vaccines (PCVs) have greatly reduced the incidence of pneumococcal disease, yet unmet medical need remains due to increased disease caused by non-vaccine serotypes (STs). V114 (VAXNEUVANCETM, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA) is a 15-valent PCV containing 13 serotypes in licensed PCV13 and 2 additional serotypes (22F, 33F) which significantly contribute to pneumococcal disease burden. This phase 3 trial compared safety, tolerability, and immunogenicity of V114 to PCV13 in adults ≥50 years of age. MethodsAdults were randomized 1:1 to receive a single dose of V114 or PCV13; randomization was stratified by age (50–64 years, 65–74 years, and ≥75 years). Adverse events (AEs) were collected following vaccination. Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) antibodies were measured prior to and 30 days after vaccination (Day 30). Primary objectives included assessing noninferiority of V114 to PCV13 for the 13 shared serotypes and superiority of V114 to PCV13 for the two unique serotypes. Superiority of V114 to PCV13 for shared serotype 3 was assessed as a secondary objective. ResultsOverall, 1,202 participants were vaccinated (V114 N = 602, PCV13 N = 600). The most commonly reported AEs across both groups were injection-site pain, fatigue, and myalgia. V114 met noninferiority criteria compared to PCV13 for the 13 shared serotypes (using a 2-fold non-inferiority margin for the ratio of OPA geometric mean titers [GMTs] [V114/PCV13] at Day 30) and met superiority for the 2 unique serotypes (using a 2-fold super-superiority margin for the ratio of OPA GMTs [V114/PCV13] at Day 30 and a 0.10 super-superiority margin for the difference in proportions of participants with ≥4-fold rise from prevaccination to Day 30). V114 met superiority criteria compared to PCV13 for serotype 3 (based on a super-superiority margin of 1.2 for the ratio of the OPA GMTs [V114/PCV13] and a superiority margin of 0 for the difference in proportions of participants with ≥4-fold rise). [NCT03950622, EudraCT#2018-004316-22, Japic-CTI#194845].

Identification of anti-horn fly vaccine antigen candidates using a reverse vaccinology approach

BackgroundThe horn fly, Haematobia irritans irritans, causes significant production losses to the cattle industry. Horn fly control relies on insecticides; however, alternative control methods such as vaccines are needed due to the fly's capacity to quickly develop resistance to insecticides, and the pressure for eco-friendly options.MethodsWe used a reverse vaccinology approach comprising three vaccine prediction and 11 annotation tools to evaluate and rank 79,542 translated open reading frames (ORFs) from the horn fly's transcriptome, and selected 10 transcript ORFs as vaccine candidates for expression in Pichia pastoris. The expression of the 10 selected transcripts and the proteins that they encoded were investigated in adult flies by reverse transcription polymerase chain reaction (RT-PCR) and mass spectrometry, respectively. Then, we evaluated the immunogenicity of a vaccine candidate in an immunization trial and the antigen’s effects on horn fly mortality and fecundity in an in vitro feeding assay.ResultsSix of the ten vaccine candidate antigens were successfully expressed in P. pastoris. RT-PCR confirmed the expression of all six ORFs in adult fly RNA. One of the vaccine candidate antigens, BI-HS009, was expressed in sufficient quantity for immunogenicity and efficacy trials. The IgG titers of animals vaccinated with BI-HS009 plus adjuvant were significantly higher than those of animals vaccinated with buffer plus adjuvant only from days 42 to 112, with a peak on day 56. Progeny of horn flies feeding upon blood from animals vaccinated with BI-HS009 plus adjuvant collected on day 56 had 63% lower pupariation rate and 57% lower adult emergence than the control group (ANOVA: F(1, 6) = 8.221, P = 0.028 and F(1, 6) = 8.299, P = 0.028, respectively).ConclusionsThe reverse vaccinology approach streamlined the discovery process by prioritizing possible vaccine antigen candidates. Through a thoughtful process of selection and in vivo and in vitro evaluations, we were able to identify a promising antigen for an anti-horn fly vaccine.Graphical abstract

Adolescent Health Series: HPV infection and vaccination in sub-Saharan Africa: 10 years of research in Tanzanian female adolescents - narrative review.

Cervical cancer is the leading cause of cancer-related morbidity and mortality in many sub-Saharan African (SSA) countries, including Tanzania. Most cervical cancer cases worldwide are attributable to infection of the cervix with Human Papillomavirus (HPV), a vaccine-preventable sexually transmitted infection (STI). Over the past 10years, we have conducted a programme of HPV research in pre-adolescents and adolescents in Mwanza, the second-largest city in Tanzania, which is situated in a malaria-endemic region. In this narrative review article, we summarise the contribution of our work, alongside work of others, to improve the understanding of HPV epidemiology in SSA and development of setting-appropriate, evidence-based intervention strategies. We present evidence for very high prevalence and incidence of HPV infection among female SSA adolescents around the time of sexual debut, describe risk factors for HPV acquisition, and discuss associations between HPV, HIV and other STIs, which are also highly prevalent within this population. We summarise findings from early clinical trials of HPV vaccines in SSA, the first of which was an immunogenicity and safety trial conducted in Mwanza, Tanzania, and Dakar, Senegal. Within the trial, we evaluated for the first time the potential impact of malaria and helminth infection on vaccine-induced antibody responses in Tanzanian girls. We describe research evaluating optimal HPV vaccine delivery strategies within this setting, perceived requirements for and barriers to vaccine implementation among key informants from LMIC, vaccine acceptability among girls and parents, and opportunities for co-delivery of interventions alongside HPV vaccination to an adolescent population. Finally, we discuss country-level barriers to vaccine uptake in LMIC, and ongoing studies in Tanzania and other SSA countries of reduced-dose HPV vaccination schedules that may alleviate cost and logistical barriers to vaccine implementation.

Where to Next? Research Directions after the First Hepatitis C Vaccine Efficacy Trial.

Thirty years after its discovery, the hepatitis C virus (HCV) remains a leading cause of liver disease worldwide. Given that many countries continue to experience high rates of transmission despite the availability of potent antiviral therapies, an effective vaccine is seen as critical for the elimination of HCV. The recent failure of the first vaccine efficacy trial for the prevention of chronic HCV confirmed suspicions that this virus will be a challenging vaccine target. Here, we examine the published data from this first efficacy trial along with the earlier clinical and pre-clinical studies of the vaccine candidate and then discuss three key research directions expected to be important in ongoing and future HCV vaccine development. These include the following: 1. design of novel immunogens that generate immune responses to genetically diverse HCV genotypes and subtypes, 2. strategies to elicit broadly neutralizing antibodies against envelope glycoproteins in addition to cytotoxic and helper T cell responses, and 3. consideration of the unique immunological status of individuals most at risk for HCV infection, including those who inject drugs, in vaccine platform development and early immunogenicity trials.

Immunogenicity of the Novel Glucagon Analogue Dasiglucagon: Results of a Dedicated Immunogenicity Trial in Type 1 Diabetes.

Dasiglucagon is a next-generation glucagon analogue that is stable in aqueous formulation. This dedicated immunogenicity trial to support use as rescue treatment for severe hypoglycemia was conducted to evaluate the immunogenicity of repeated subcutaneous doses of dasiglucagon in subjects with type 1 diabetes. A total of 112 subjects were randomized 1:1 to receive three subcutaneous weekly doses of either 0.6 mg dasiglucagon or 1.0 mg recombinant glucagon (GlucaGen®) according to a double-blind parallel-group trial design. Subjects were followed for 15 weeks, with a multitiered testing approach planned for assessment of antidrug antibody (ADA) formation. For the primary immunogenicity endpoint, the overall ADA incidence was zero, as no subject demonstrated any treatment-induced or treatment-boosted ADA response at any time point in this trial involving three consecutive weekly doses of trial drug. No injection site reactions were reported for subjects receiving dasiglucagon. There were no unexpected safety findings for the trial.

Safety and immunogenicity of ChAd63-KH vaccine in post-kala-azar dermal leishmaniasis patients in Sudan

Post-kala-azar dermal leishmaniasis (PKDL) is a chronic, stigmatizing skin condition occurring frequently after apparent clinical cure from visceral leishmaniasis. Given an urgent need for new treatments, we conducted a phase IIa safety and immunogenicity trial of ChAd63-KH vaccine in Sudanese patients with persistent PKDL. LEISH2a (ClinicalTrials.gov: NCT02894008) was an open-label three-phase clinical trial involving sixteen adult and eight adolescent patients with persistent PKDL (median duration, 30 months; range, 6–180 months). Patients received a single intramuscular vaccination of 1 × 1010 viral particles (v.p.; adults only) or 7.5 × 1010 v.p. (adults and adolescents), with primary (safety) and secondary (clinical response and immunogenicity) endpoints evaluated over 42–120 days follow-up. AmBisome was provided to patients with significant remaining disease at their last visit. ChAd63-KH vaccine showed minimal adverse reactions in PKDL patients and induced potent innate and cell-mediated immune responses measured by whole-blood transcriptomics and ELISpot. 7/23 patients (30.4%) monitored to study completion showed >90% clinical improvement, and 5/23 (21.7%) showed partial improvement. A logistic regression model applied to blood transcriptomic data identified immune modules predictive of patients with >90% clinical improvement. A randomized controlled trial to determine whether these clinical responses were vaccine-related and whether ChAd63-KH vaccine has clinical utility is underway.

A comparison of multivalent and bivalent vaccination strategies for the control of virulent ovine footrot

Virulent footrot is a significant economic and animal welfare concern. The disease can be treated, controlled, and eliminated with vaccine, but selecting the appropriate vaccination strategy can be challenging. There are two main strategies: outbreak (serogroup)-specific univalent or bivalent vaccination, or use of a multivalent vaccine containing up to nine of the most common serogroups. The objective of this study was to compare these approaches in sheep flocks infected with multiple Dichelobacter nodosus serogroups. In the first phase, we undertook an immunogenicity trial in which we compared four pre-commercial multivalent recombinant fimbrial vaccines containing six (A, B, C, G, H, I) or nine (A, B, C, D, E, F, G, H, I) serogroups, and compared them to commercial bivalent vaccines. Two multivalent vaccines stimulated significantly higher antibody responses than two other multivalent vaccines but the number of serogroups included in the multivalent vaccine formulations did not have a significant effect. In the first phase, we also compared inter-vaccination intervals of two- and three-months between sequential bivalent vaccines, and found that a two-month interval was sufficient to avoid antigenic competition. In the second phase, the most immunogenic multivalent vaccine (nine serogroups) was compared to sequential bivalent vaccines and monthly foot-bathing in a field trial in four commercial Merino flocks. The duration of protection afforded by the multivalent vaccine was likely to be less than that of the bivalent vaccines, as the antibody titres stimulated were lower and less persistent.

Estimation of the correlates of protection of the rVSVΔG-ZEBOV-GP Zaire ebolavirus vaccine: a post-hoc analysis of data from phase 2/3 clinical trials

Establishment of immune correlates of protection can provide a measurable criterion for assessing protection against infection or disease. For some vaccines, such as the measles vaccine, antibodies serve as the correlate of protection, but for others, such as human papillomavirus, the correlate of protection remains unknown. Merck & Co, Kenilworth, NJ, USA, in collaboration with multiple partners, developed a live recombinant vesicular stomatitis virus vaccine (rVSVΔG-ZEBOV-GP [ERVEBO]) containing the Zaire ebolavirus glycoprotein (GP) in place of the recombinant vesicular stomatitis virus GP to prevent Ebola virus disease. Seroresponse, defined as post-vaccination GP-ELISA of 200 ELISA units (EU) per mL or higher and two-times or more above baseline, was proposed; however, correlates of protection have not been determined. The objective of this post-hoc analysis was to infer possible correlates of protection for rVSVΔG-ZEBOV-GP. In this post-hoc analysis we included vaccinated participants with serology data from three phase 2/3 immunogenicity trials in Guinea, Sierra Leone, and Liberia (n=2199). Two of the trials were open-label, single-arm trials (one randomised [STRIVE], one non-randomised [FLW]); and one trial was randomised, placebo-controlled with two vaccine comparators (PREVAIL). Endpoints were total IgG antibody response (EU per mL) to rVSVΔG-ZEBOV-GP measured by GP-ELISA and neutralising antibody response to rVSVΔG-ZEBOV-GP measured by plaque reduction neutralisation test at days 14, 28, 180, and 365 after vaccination. Reverse cumulative distribution curves of the antibody concentrations were used to estimate statistical correlates of protection between 70% and 100% that might be applied to vaccine efficacy and effectiveness estimates. Although GP-ELISA and plaque reduction neutralisation tests showed similar response patterns, GP-ELISA provided a wider range of measurable titres and better differentiation for estimating correlates of protection compared with the plaque reduction neutralisation test. At day 14 after vaccination in the FLW trial, 1060 (100%) of 1060 participants had GP-ELISA levels at or above 68 EU per mL and 742 (70%) of 1060 had levels at or above 313 EU per mL. At day 28 after vaccination in the pooled population, 1953 (100%) of 1953 participants had levels at or above 73 EU per mL and 1368 (70%) of 1953 participants had levels at or above 735 EU per mL. GP-ELISA seroresponse 200 EU per mL or higher and two-times or more increase in antibody level from baseline occurred in 80% or higher of participants at each assessment and in 94% or higher of participants at any time after vaccination. Our results are consistent with previous work suggesting that seroresponse defined as GP-ELISA of 200 EU per mL or higher and two-times or more from baseline associated with vaccination might be the most appropriate dichotomous correlate of protection and falls within the seroprotective threshold range described herein. Merck Sharp & Dohme, Biomedical Advanced Research and Development Authority, Office of the Assistant Secretary for Preparedness and Response, US Department of Health and Human Services.

Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial

BackgroundTo mitigate the effects of COVID-19, a vaccine is urgently needed. BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine formulated with a toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG) or alum (Algel).MethodsWe did a double-blind, multicentre, randomised, controlled phase 1 trial to assess the safety and immunogenicity of BBV152 at 11 hospitals across India. Healthy adults aged 18–55 years who were deemed healthy by the investigator were eligible. Individuals with positive SARS-CoV-2 nucleic acid and/or serology tests were excluded. Participants were randomly assigned to receive either one of three vaccine formulations (3 μg with Algel-IMDG, 6 μg with Algel-IMDG, or 6 μg with Algel) or an Algel only control vaccine group. Block randomisation was done with a web response platform. Participants and investigators were masked to treatment group allocation. Two intramuscular doses of vaccines were administered on day 0 (the day of randomisation) and day 14. Primary outcomes were solicited local and systemic reactogenicity events at 2 h and 7 days after vaccination and throughout the full study duration, including serious adverse events. Secondary outcome was seroconversion (at least four-fold increase from baseline) based on wild-type virus neutralisation. Cell-mediated responses were evaluated by intracellular staining and ELISpot. The trial is registered at ClinicalTrials.gov (NCT04471519).FindingsBetween July 13 and 30, 2020, 827 participants were screened, of whom 375 were enrolled. Among the enrolled participants, 100 each were randomly assigned to the three vaccine groups, and 75 were randomly assigned to the control group (Algel only). After both doses, solicited local and systemic adverse reactions were reported by 17 (17%; 95% CI 10·5–26·1) participants in the 3 μg with Algel-IMDG group, 21 (21%; 13·8–30·5) in the 6 μg with Algel-IMDG group, 14 (14%; 8·1–22·7) in the 6 μg with Algel group, and ten (10%; 6·9–23·6) in the Algel-only group. The most common solicited adverse events were injection site pain (17 [5%] of 375 participants), headache (13 [3%]), fatigue (11 [3%]), fever (nine [2%]), and nausea or vomiting (seven [2%]). All solicited adverse events were mild (43 [69%] of 62) or moderate (19 [31%]) and were more frequent after the first dose. One serious adverse event of viral pneumonitis was reported in the 6 μg with Algel group, unrelated to the vaccine. Seroconversion rates (%) were 87·9, 91·9, and 82·8 in the 3 μg with Algel-IMDG, 6 μg with Algel-IMDG, and 6 μg with Algel groups, respectively. CD4+ and CD8+ T-cell responses were detected in a subset of 16 participants from both Algel-IMDG groups.InterpretationBBV152 led to tolerable safety outcomes and enhanced immune responses. Both Algel-IMDG formulations were selected for phase 2 immunogenicity trials. Further efficacy trials are warranted.FundingBharat Biotech International.

Broad cross-national public support for accelerated COVID-19 vaccine trial designs

A vaccine for COVID-19 is urgently needed. Several vaccine trial designs may significantly accelerate vaccine testing and approval, but also increase risks to human subjects. Concerns about whether the public would see such designs as ethical represent an important roadblock to their implementation; accordingly, both the World Health Organization and numerous scholars have called for consulting the public regarding them. We answered these calls by conducting a cross-national survey (n = 5920) in Australia, Canada, Hong Kong, New Zealand, South Africa, Singapore, the United Kingdom, and the United States. The survey explained key differences between traditional vaccine trials and two accelerated designs: a challenge trial or a trial integrating a Phase II safety and immunogenicity trial into a larger Phase III efficacy trial. Respondents’ answers to comprehension questions indicate that they largely understood the key differences and ethical trade-offs between the designs from our descriptions. We asked respondents whether they would prefer scientists to conduct traditional trials or one of these two accelerated designs. We found broad majorities prefer for scientists to conduct challenge trials (75%) and integrated trials (63%) over standard trials. Even as respondents acknowledged the risks, they perceived both accelerated trials as similarly ethical to standard trial designs. This high support is consistent across every geography and demographic subgroup we examined, including vulnerable populations. These findings may help assuage some of the concerns surrounding accelerated designs.

Safety and Immunogenicity Trial of an Inactivated SARS-CoV-2 Vaccine-BBV152: A Phase 1, Double-Blind, Randomised Control Trial

Background: BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 μg or 6 μg) formulated with a Toll-Like Receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG) or 6 μg with alum (Algel).Methods: We conducted a double-blind, randomised, multicentre, controlled phase 1 clinical trial to evaluate the safety and immunogenicity of BBV152. A total of 375 healthy adults Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation were randomised equally to receive three vaccine formulations (n=100 each) prepared with 3 μg with Algel-IMDG, 6 μg with Algel-IMDG, and 6 μg with Algel, and an Algel only control arm (n=75). Two intramuscular doses of vaccines were administered (twoweeks apart). Primary outcomes were reactogenicity and safety. Secondary outcome was seroconversion (≥4-fold above baseline) based on wild-type virus neutralisation. Cell-mediated responses were evaluated by intracellular staining and ELISpot.Findings: Among 827 participants screened between July 13 and July 30, 2020, 375 participants were randomised. After both doses, the proportion (95%CI) of solicited local and systemic adverse reactions were 17% (10·5, 26·1), 21% (13·8, 30·5), 14% (8·1, 22·7), and 10% (6·9, 23·6) in the 3 μg with Algel-IMDG, 6 μg with Algel-IMDG, 6 μg with Algel, and control groups, respectively . The most common solicited adverse events were injection site pain, headache, and fatigue. All solicited adverse events were mild (43, 69·3%) or moderate (19, 30·7%) and were more frequent after the first dose. One serious adverse event was reported in the 6 μg with Algel group, unrelated to the vaccine. Seroconversion rates (%) were 87·9, 91·9, and 82·8 in the 3 μg with AlgelIMDG, 6 μg with Algel-IMDG and 6 μg with Algel groups, respectively. CD4 + and CD8 + T cell responses were detected in a subset from both Algel-IMDG groups.Interpretations: BBV152 led to tolerable safety outcomes and enhanced immune responses. Both Algel-IMDG formulations were selected for phase 2 immunogenicity trials. Further efficacy trials are warranted.Trial Registration Number: Clinicaltrials.gov : NCT04471519 Funding: This work was supported and funded by Bharat Biotech International Limited. Conflict of Interest: This work was supported and funded by Bharat Biotech International Limited. All authors are employees of one of the above-mentioned organisations, with no stock options or incentives. Co-author- K.E is the Chairman and Managing Director of Bharat Biotech.Ethical Approval: The trial was conducted across 11 sites in 9 states in India. The trial was approved by the National Regulatory Authority (India) and the respective Ethics Committees and was conducted in compliance with all International Council for Harmonization 114 (ICH) Good Clinical Practice guidelines.

Induction of Cross-Reactive Hemagglutination Inhibiting Antibody and Polyfunctional CD4+ T-Cell Responses by a Recombinant Matrix-M-Adjuvanted Hemagglutinin Nanoparticle Influenza Vaccine.

BackgroundRecurrent reports of suboptimal influenza vaccine effectiveness have renewed calls to develop improved, broadly cross-protective influenza vaccines. Here, we evaluated the safety and immunogenicity of a novel, saponin (Matrix-M)–adjuvanted, recombinant hemagglutinin (HA) quadrivalent nanoparticle influenza vaccine (qNIV).MethodsWe conducted a randomized, observer-blind, comparator-controlled (trivalent high-dose inactivated influenza vaccine [IIV3-HD] or quadrivalent recombinant influenza vaccine [RIV4]), safety and immunogenicity trial of qNIV (5 doses/formulations) in healthy adults ≥65 years. Vaccine immunogenicity was measured by hemagglutination-inhibition assays using reagents that express wild-type hemagglutination inhibition (wt-HAI) sequences and cell-mediated immune responses.ResultsA total of 1375 participants were randomized, immunized, and followed for safety and immunogenicity. Matrix-M–adjuvanted qNIV induced superior wt-HAI antibody responses against 5 of 6 homologous or drifted strains compared with unadjuvanted qNIV. Adjuvanted qNIV induced post-vaccination wt-HAI antibody responses at day 28 that were statistically higher than IIV3-HD against a panel of homologous or drifted A/H3N2 strains, similar to IIV3-HD against homologous A/H1N1 and B (Victoria) strains and similar to RIV4 against all homologous and drifted strains evaluated. The qNIV formulation with 75 µg Matrix-M adjuvant induced substantially higher post-vaccination geometric mean fold increases of influenza HA-specific polyfunctional CD4+ T cells compared with IIV3-HD or RIV4. Overall, similar frequencies of solicited and unsolicited adverse events were reported in all treatment groups.ConclusionsqNIV with 75 µg Matrix-M adjuvant was well tolerated and induced robust antibody and cellular responses, notably against both homologous and drifted A/H3N2 viruses. Further investigation in a pivotal phase 3 trial is underway.Clinical Trials RegistrationNCT03658629.

Acceptability of an inactivated influenza vaccine delivered by microneedle patch: Results from a phase I clinical trial of safety, reactogenicity, and immunogenicity

ObjectiveThis study sought to evaluate the acceptability of inactivated influenza vaccine delivered by microneedle patch (MNP) in comparison to inactivated influenza vaccine (IIV) delivered by hypodermic needle.Design, Setting, and Participants.From the general population of Atlanta, Georgia, we screened 112 and enrolled 100 healthy adult subjects ages 18 to 49 years.Main Outcome(s) and Measure(s).Our participants were randomized to 4 groups of 25 per arm: (1) IIV by MNP administered by healthcare worker (HCW), (2) IIV by MNP self-administered by study participants, (3) IIV by intramuscular (IM) injection administered by HCW or (4) placebo by MNP administered by HCW. We administered four questionnaires: at Day 0 before and after study product delivery, and at Days 8 and 28. ResultsAt baseline, 98.6% of participants receiving MNP vaccination reported an overall positive experience with MNPs, compared to 86.4% for participants receiving IM vaccination. For future influenza vaccination, study participants (N = 99) preferred MNP (n = 65, 69.9%) to injections or nasal spray (n = 20, 21.5%), and the preference for MNP increased from Day 0 to Day 28. Factor analyses resulted in two scaled measures including MNP Use Perceptions (a = 0.799, n = 5 items) and MNP Perceived Convenience (a = 0.844, n = 4 items) that were included in longitudinal assessments; while findings reflect significant differences across treatment groups on mean scores for ease of use, MNP perceived protection, MNP reliability, and MNP selection knowledge, all groups reported their belief that influenza vaccination by MNP would be reliable and protective, as well as easy-to-use and convenient. Conclusions and RelevanceMost participants were accepting of IIV vaccination by MNP and preferred it to injection. Delivery of IIV by MNP may help increase vaccination coverage.

Feasibility of direct venous inoculation of the radiation-attenuated Plasmodium falciparum whole sporozoite vaccine in children and infants in Siaya, western Kenya

PfSPZ Vaccine, composed of radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum sporozoites, is administered by direct venous inoculation (DVI) for maximal efficacy against malaria. A critical issue for advancing vaccines that are administered intravenously is the ability to efficiently administer them across multiple age groups. As part of a pediatric safety, immunogenicity, and efficacy trial in western Kenya, we evaluated the feasibility and tolerability of DVI, including ease of venous access, injection time, and crying during the procedure across age groups. Part 1 was an age de-escalation, dose escalation trial in children aged 13 months-5 years and infants aged 5–12 months; part 2 was a vaccine efficacy trial including only infants, using the most skilled injectors from part 1. Injectors could use a vein viewer, if needed. A total of 1222 injections (target 0.5 mL) were initiated by DVI in 511 participants (36 were 5–9-year-olds, 65 were 13–59-month-olds, and 410 infants). The complete volume was injected in 1185/1222 (97.0%) vaccinations, 1083/1185 (91.4%) achieved with the first DVI. 474/511 (92.8%) participants received only complete injections, 27/511 (5.3%) received at least one partial injection (<0.5 mL), and in 10/511 (2.0%) venous access was not obtained. The rate of complete injections by single DVI for infants improved from 77.1% in part 1 to 92.8% in part 2. No crying occurred in 51/59 (86.4%) vaccinations in 5–9-year-olds, 25/86 (29.1%) vaccinations in 13–59-month-olds and 172/1067 (16.1%) vaccinations in infants. Mean administration time ranged from 2.6 to 4.6 minutes and was longer for younger age groups.These data show that vaccination by DVI was feasible and well tolerated in infants and children in this rural hospital in western Kenya, when performed by skilled injectors. We also report that shipping and storage in liquid nitrogen vapor phase was simple and efficient. (Clinicaltrials.gov NCT02687373).

Arranging good clinical practices training and trial monitoring for a vaccine efficacy study during a public health emergency of international concern

The 2014–2015 outbreak of Ebola Virus Disease (EVD) in West Africa was unprecedented in size and scope. The World Health Organization, government of Guinea and other partners undertook a field trial of efficacy of an Ebola vaccine in Guinea, with a parallel immunogenicity study in front-line workers. However, several obstacles had to be overcome. One was the need to teach Good Clinical Practices to a large group of field workers who had never participated in vaccine clinical trial research. Because the trial design was complex, performing this efficacy trial during an Ebola outbreak would have been challenging even for experienced investigators. For field workers who had never previously participated in a clinical trial, this constituted a daunting challenge. Another challenge was to provide independent monitoring to document the quality and validity of the field trial data to support future regulatory agency licensure. Here we discuss how these challenges were overcome, and what lessons can be drawn for the future. Intensive GCP was expeditiously arranged for 251 clinical study staff on-site in Guinea. The trials were initiated within days after completion of training. Monitoring (100% of participants in the efficacy trial and 50% in the immunogenicity trial) began at the onset of the trials. Early monitoring detected many minor errors but prompt feedback and guidance from the monitors, who explained the mistakes and proposed corrective actions, diminished error frequency as the trials progressed. Monitoring later in the trials showed what one would expect in a study conducted by experienced investigators. Should a vaccine field trial have to be hastily arranged during a future emerging disease outbreak in a developing country setting, our methods of training and monitoring could provide a model.

Clinical trial to assess immunogenicity of high-dose, adjuvanted, and recombinant influenza vaccines against cell-grown A(H3N2) viruses in adults 65 to 74 years, 2017–2018

BackgroundLicensed inactivated influenza vaccines (IIV) are recommended for persons aged ≥65 years, including trivalent high-dose IIV (HD-IIV3) and adjuvanted IIV (aIIV3); both are manufactured in eggs. Quadrivalent recombinant vaccine (RIV4) is produced without eggs. We conducted an exploratory study to compare immunogenicity of HD-IIV3, aIIV3 and RIV4 against cell-grown vaccine and circulating A(H3N2) viruses in 2017–18. MethodsEighty-nine adults aged 65–74 years participating in a 2-year, open-label immunogenicity trial (ClinicalTrails.gov: NCT02872311) were randomized 1:1:1 to receive HD-IIV3, aIIV3, or RIV4 after receipt of standard dose IIV3 in 2016–17. Serum was obtained at baseline and day 28 post vaccination. Microneutralization titers were determined using four cell-propagated A(H3N2) viruses: 2017–18 vaccine strain (clade 3C.2a), circulating viruses from clades 3C.2a1 and 3C.2a2, and ‘antigenically advanced’ clade 3C.3a (2019–20 vaccine strain). Active surveillance was conducted to identify influenza illnesses. ResultsPost vaccination geometric mean titer (GMT) against the vaccine strain was <1:60 in each group and <15% seroconverted. RIV4 generated a greater fold-rise (2.0, 95% CI 1.7–2.5) compared to HD-IIV3 (1.6, 95% CI 1.3–1.8). RIV4 generated higher post vaccination titers against 3C.2a1 and 3C.2a2 viruses, and the mean fold-rise after RIV4 was twice as high (3.3 and 3.5, respectively) relative to HD-IIV3 (1.4 and 1.6) and aIIV3 (1.7 and 1.6). Against the antigenically advanced 3C.3a virus, RIV4 generated a greater mean fold-rise (2.9, 95% CI 2.0–4.3) vs HD-IIV3 (1.3, 95% CI 1.1–1.6) and aIIV3 (1.7, 95% CI 1.3–2.1). Postvaccination titers against 3C.2a2 were ≥1:40 in 5 of 7 participants with PCR-confirmed A(H3N2) infection during the ensuing influenza season. ConclusionHigh-dose, adjuvanted, and recombinant vaccines generated suboptimal neutralizing antibody responses to the cell-grown vaccine strain, but RIV4 generated a greater cross-protective response against circulating and antigenically advanced viruses. Recombinant technology may contribute to more broadly protective influenza vaccines, and comparative effectiveness studies are needed.

Factors influencing participation in an Ebola vaccine trial among front-line workers in Guinea

BackgroundAlongside the clinical aspects of the immunogenicity and safety trial of an Ebola vaccine deployed among front-line workers, a qualitative study was conducted to describe motivations behind individuals’ decisions to participate – or not to participate – in the study. MethodsIn July and August 2015, focus group discussions and semi-structured individual interviews were conducted in Conakry, Guinea. Individuals were eligible for the qualitative study if they met the inclusion criteria of the immunogenicity and safety study irrespective of their participation. Surveys were also conducted among several institution and department heads of staff included in the study as well as vaccine trial staff members. Discussion and interview transcripts were analyzed using content thematic analysis. ResultsInterviews and focus groups were conducted among 110 persons, of whom about two-thirds (67%) participated in the vaccine trial. There was at least one group interview conducted at each participating trial site, along with numerous formal and informal interviews and conversations through the enrollment period. Participants were often motivated by a desire to save and protect themselves and others, contribute to scientific progress, or lead by example. Non-participants expressed concerns regarding the risk and costs of participation, particularly the fear of unknown side effects following vaccination, and distrust or fear of stigmatization. ConclusionsDespite the unique nature of the 2014–2015 Ebola outbreak, front-line workers employed much of the same logic when choosing to participate as in other clinical trials in similar settings. Special consideration should be given to addressing perceived inequity, misunderstanding, and mistrust among the target populations in future trials.Clinical trial registry number: This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193.

Combining antimalarial drugs and vaccine for malaria elimination campaigns: a randomized safety and immunogenicity trial of RTS,S/AS01 administered with dihydroartemisinin, piperaquine, and primaquine in healthy Thai adult volunteers

ABSTRACTIntroduction: RTS,S/AS01 is currently the most advanced malaria vaccine but provides incomplete, short-term protection. It was developed for use within the expanded program on immunizations (EPI) for African children. Another use could be adding mass RTS,S/AS01 vaccination to the integrated malaria elimination strategy in the Greater Mekong Subregion (GMS), where multidrug-resistant P.falciparum strains have emerged and spread. Prior to evaluating RTS,S/AS01 in large-scale trials we assessed whether the vaccine, administered with and without antimalarial drugs, is safe and immunogenic in Asian populations.Methods: An open-label, randomized, controlled phase 2 trial was conducted in healthy, adult Thai volunteers. Seven vaccine regimens with and without antimalarial drugs (dihydroartemisinin-piperaquine plus a single low dose primaquine) were assessed. Antibody titres against the PfCSP full-length (NANP) 6, PfCSP anti-C–term, PfCSP full-length (N + C-Terminal) were measured by standard enzyme-linked immunosorbent assays. Liquid chromatography was used to measure piperaquine, primaquine and carboxy-primaquine concentrations.Results: 193 volunteers were enrolled and 186 study participants completed the 6 months follow-up period. One month after the last vaccination all study participants had seroconverted to the PfCSP (NANP)6, and the PfCSP Full Length (N + C-Terminal). More than 90% had seroconverted to the Pfanti-C-Term CSP. There was no indication that drug concentrations were influenced by vaccine regimens or the antibody levels by the drug regimens. Adverse events were similarly distributed between the seven treatment groups. No serious adverse events attributable to the study interventions were detected.Conclusion: This study found that RTS,S/AS01 with and without dihydroartemisinin-piperaquine plus a single low dose primaquine was safe and immunogenic in a healthy, adult Asian population.

Phase II Clinical Trial of Safety and Immunogenicity of Recombinant Subunit Tuberculosis Vaccine GamTBvac

Phase II Clinical Trial of Safety and Immunogenicity of Recombinant Subunit Tuberculosis Vaccine GamTBvac

991. Randomized Trial of High Dose, Adjuvanted, and Standard Inactivated Influenza Vaccine Immune Response Against Egg- and Cell-Propagated Vaccine Strains in Older Adults, 2016–2017 Season

BackgroundHigh dose (HD-IIV), standard dose (SD-IIV), and MF-59 adjuvanted (aIIV) influenza vaccines are licensed for adults ≥65 years old, but there is no preferential recommendation for a specific product. These vaccines are manufactured using egg-adapted high growth reassortant viruses. Recent data suggest that antibodies generated by egg-adapted A(H3N2) viruses may contribute to reduced vaccine effectiveness. We report results from the first year of a 2-year randomized trial of vaccine immunogenicity, including response to A(H3N2) vaccine strains propagated in egg (H3N2-egg) and cell culture (H3N2-cell).MethodsAdults 65–74 years old were randomized to receive 2016–2017 trivalent inactivated influenza vaccines: SD-IIV (n = 60), HD-IIV (n = 59), and aIIV (n = 60). Pre- and post-vaccination sera were analyzed by microneutralization assays (MN) to egg- and cell-propagated A(H3N2) vaccine virus, A/Hong Kong/4801/2014 and tested by hemagglutination inhibition (HI) assays to A/California/7/2009 A(H1N1)pdm09-like and B/Brisbane/60/2008-like viruses. Endpoints were postvaccination geometric mean titer (GMT), mean fold rise (MFR), and seroconversion. Respiratory swabs from adults with acute respiratory illness during the season were tested by RT-PCR to identify vaccine failures.ResultsPrevaccination MN and HI titers were similar across study arms. There were no differences across study arms in postvaccination MN GMT, seroconversion, and MFR against H3N2-egg and H3N2-cell (figure). However, response was lower against H3N2-cell than H3N2-egg. HI MFR for H1N1pdm09 and B/Brisbane were significantly higher in HD-IIV than SD-IIV and aIIV recipients (figure). Eight participants had PCR-confirmed A(H3N2) infection: 1/60 (2%) SD-IIV, 4/57 (7%) HD-IIV, and 3/60 (5%) aIIV recipients. Postvaccination H3N2-cell MN GMT was 15 and 63, respectively for A(H3N2) cases and noncases. Among the eight A(H3N2) cases, postvaccination MN titers were ≥1:40 against H3N2-egg for 6 cases vs. 0 cases against H3N2-cell.ConclusionPostvaccination MN titers against H3N2 egg- and cell-propagated vaccine viruses were similar across study arms, although antibody response was lower to H3N2-cell. HD-IIV generated greater antibody response against A(H1N1)pdm09 and B compared with SD-IIV or aIIV.Disclosures All authors: No reported disclosures.