Accelerate Vaccine Development Research Articles

What Gastroenterologists Should Know About COVID-19 Vaccines

What Gastroenterologists Should Know About COVID-19 Vaccines

A short discussion about the SARS-CoV-2 mRNA-1273 vaccine

The COVID-19 global pandemic has prompted accelerated vaccine development efforts. This perspective discusses the importance of SARS-CoV-2 vaccine candidates’ recruitment of cellular T-cell immunity and encourages industry to increasingly investigate and publish parameters related to cellular immunity in their research reports.

Characterization of a new Leishmania major strain for use in a controlled human infection model

Leishmaniasis is widely regarded as a vaccine-preventable disease, but the costs required to reach pivotal Phase 3 studies and uncertainty about which candidate vaccines should be progressed into human studies significantly limits progress in vaccine development for this neglected tropical disease. Controlled human infection models (CHIMs) provide a pathway for accelerating vaccine development and to more fully understand disease pathogenesis and correlates of protection. Here, we describe the isolation, characterization and GMP manufacture of a new clinical strain of Leishmania major. Two fresh strains of L. major from Israel were initially compared by genome sequencing, in vivo infectivity and drug sensitivity in mice, and development and transmission competence in sand flies, allowing one to be selected for GMP production. This study addresses a major roadblock in the development of vaccines for leishmaniasis, providing a key resource for CHIM studies of sand fly transmitted cutaneous leishmaniasis.

Controlled Infection of Humans with the Hookworm Parasite Necator americanus to Accelerate Vaccine Development : The Human Hookworm Vaccination/Challenge Model (HVCM).

In this chapter, we describe the scientific, technical, clinical and regulatory aspects of establishing a controlled human hookworm infection (CHHI) model in non-endemic and endemic geographical regions, to facilitate a pathway towards accelerated vaccine development. The success achieved in establishing the CHHI platform specifically allows the Human Hookworm Vaccine Initiative (HHVI) to accelerate its progress by establishing a human hookworm vaccination/challenge model (HVCM) in a hookworm endemic area of Brazil. The HVCM will permit the rapid and robust determination of clinical efficacy in adults, allowing for early selection of the most efficacious human hookworm vaccine (HHV) candidate(s) to advance into later-stage pivotal paediatric clinical trials and reduce the overall number of participants required to assess efficacy (Diemert et al. 2018).

Human Challenge Studies for Vaccine Development : Regulatory Aspects of Human Challenge Studies.

The traditional regulatory pathway for the evaluation of new vaccine candidates generally proceeds from preclinical through three successive phases of human trials, and the demonstration of efficacy is usually done through randomized-controlled clinical trials. However, human challenge trials or controlled human infection models have been used in vaccine clinical development to generate supportive data for establishment of correlates of protection, supportive data for licensure, as well as licensure in the case of Vaxchora® by the US FDA. Despite this, there are no codified regulations from national regulatory authorities (NRAs) that specifically address HCTs, nor guidance related to standardization of approaches to HCTs among regulators. NRAs may agree that HCTs are innovative, promising tools to accelerate vaccine development; however, a strong benefit/risk assessment is needed to ensure the safety of study participants. Lastly, it is important to consider the regulatory framework in which the human challenge trial may be conducted.

P. falciparum and P. vivax Orthologous Coiled-Coil Candidates for a Potential Cross-Protective Vaccine.

Over the last four decades, significant efforts have been invested to develop vaccines against malaria. Although most efforts are focused on the development of P. falciparum vaccines, the current availability of the parasite genomes, bioinformatics tools, and high throughput systems for both recombinant and synthetic antigen production have helped to accelerate vaccine development against the P. vivax parasite. We have previously in silico identified several P. falciparum and P. vivax proteins containing α-helical coiled-coil motifs that represent novel putative antigens for vaccine development since they are highly immunogenic and have been associated with protection in many in vitro functional assays. Here, we selected five pairs of P. falciparum and P. vivax orthologous peptides to assess their sero-reactivity using plasma samples collected in P. falciparum- endemic African countries. Pf-Pv cross-reactivity was also investigated. The pairs Pf27/Pv27, Pf43/Pv43, and Pf45/Pv45 resulted to be the most promising candidates for a cross-protective vaccine because they showed a high degree of recognition in direct and competition ELISA assays and cross-reactivity with their respective ortholog. The recognition of P. vivax peptides by plasma of P. falciparum infected individuals indicates the existence of a high degree of cross-reactivity between these two Plasmodium species. The design of longer polypeptides combining these epitopes will allow the assessment of their immunogenicity and protective efficacy in animal models.

A Scalable Topical Vectored Vaccine Candidate against SARS-CoV-2.

The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) caused an ongoing unprecedented global public health crises of coronavirus disease in 2019 (CoVID-19). The precipitously increased death rates, its impact on livelihood and trembling economies warrant the urgent development of a SARS-CoV-2 vaccine which would be safe, efficacious and scalable. Owing to unavailability of the vaccine, we propose a de novo synthesized avian orthoavulavirus 1 (AOaV-1)-based topical respiratory vaccine candidate against CoVID-19. Avirulent strain of AOaV-1 was engineered to express full length spike (S) glycoprotein which is highly neutralizing and a major protective antigen of the SARS-CoV-2. Broad-scale in vitro characterization of a recombinant vaccine candidate demonstrated efficient co-expression of the hemagglutinin-neuraminidase (HN) of AOaV-1 and S protein of SARS-CoV-2, and comparable replication kinetics were observed in a cell culture model. The recombinant vaccine candidate virus actively replicated and spread within cells independently of exogenous trypsin. Interestingly, incorporation of S protein of SARS-CoV-2 into the recombinant AOaV-1 particles attributed the sensitivity to anti-SARS-CoV-2 antiserum and more prominently to anti-AOaV-1 antiserum. Finally, our results demonstrated that the recombinant vaccine vector stably expressed S protein after multiple propagations in chicken embryonated eggs, and this expression did not significantly impact the in vitro growth characteristics of the recombinant. Taken together, the presented respiratory vaccine candidate is highly attenuated in primates per se, safe and lacking pre-existing immunity in human, and carries the potential for accelerated vaccine development against CoVID-19 for clinical studies.

COVID-19: Mechanisms of Vaccination and Immunity.

Vaccines are needed to protect from SARS-CoV-2, the virus causing COVID-19. Vaccines that induce large quantities of high affinity virus-neutralizing antibodies may optimally prevent infection and avoid unfavorable effects. Vaccination trials require precise clinical management, complemented with detailed evaluation of safety and immune responses. Here, we review the pros and cons of available vaccine platforms and options to accelerate vaccine development towards the safe immunization of the world’s population against SARS-CoV-2. Favorable vaccines, used in well-designed vaccination strategies, may be critical for limiting harm and promoting trust and a long-term return to normal public life and economy.

Immune-mediated approaches against COVID-19.

The coronavirus disease-19 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The long incubation period of this new virus, which is mostly asymptomatic yet contagious, is a key reason for its rapid spread across the world. Currently, there is no worldwide-approved treatment for COVID-19. Therefore, the clinical and scientific communities have joint efforts to reduce the severe impact of the outbreak. Research on previous emerging infectious diseases have created valuable knowledge that is being exploited for drug repurposing and accelerated vaccine development. Nevertheless, it is important to generate knowledge on SARS-CoV-2 mechanisms of infection and its impact on host immunity, to guide the design of COVID-19 specific therapeutics and vaccines suitable for mass immunization. Nanoscale delivery systems are expected to play a paramount role in the success of these prophylactic and therapeutic approaches. This Review provides an overview of SARS-CoV-2 pathogenesis and examines immune-mediated approaches currently explored for COVID-19 treatments, with an emphasis on nanotechnological tools.

Calling for an exponential escalation scheme in vaccine development for COVID-19

PurposeCOVID-19 as a pandemic calls for rapid development of vaccines.MethodsHere a proposal of a seamless, adaptive, phase 1–3 trial for accelerated vaccine development is described.ResultsStarting at 10, the number of vaccinated volunteers would exponentially increase by tenfold at an interval of 2 weeks; close surveillance of antibody responses, safety and efficacy is necessary. After only 16 weeks, general vaccination would be feasible if supply meets the demand.ConclusionA COVID-19 vaccine would be rapidly available at a slightly increased risk for undetected late side effects or insufficient efficacy if compared with standard vaccine development schemes.

Challenges of accelerated vaccine development

Challenges of accelerated vaccine development

Safe vaccine development

Coronavirus The coronavirus disease 2019 (COVID-19) pandemic has prompted accelerated vaccine development in the hope that predicted mortality rates can be reduced and population, or herd, immunity achieved. These measures could result in eventual eradication of the disease. In a Perspective, Graham discusses the need to ensure that vaccines are safe and do not aggravate coronavirus infection. Based on lessons learned from past vaccines, various steps need to be taken to ensure that expedited vaccine development is accompanied in parallel by safety assessments to prioritize the most effective candidates. Science , this issue p. [945][1] [1]: /lookup/doi/10.1126/science.abb8923

Safety, reactogenicity, and immunogenicity of a chimpanzee adenovirus vectored Ebola vaccine in adults in Africa: a randomised, observer-blind, placebo-controlled, phase 2 trial

The 2014 Zaire Ebola virus disease epidemic accelerated vaccine development for the virus. We aimed to assess the safety, reactogenicity, and immunogenicity of one dose of monovalent, recombinant, chimpanzee adenovirus type-3 vectored Zaire Ebola glycoprotein vaccine (ChAd3-EBO-Z) in adults. This phase 2, randomised, observer-blind, controlled trial was done in study centres in Cameroon, Mali, Nigeria, and Senegal. Healthy adults (≥18 years) were randomly assigned with a web-based system (1:1; minimisation procedure accounting for age, gender, centre) to receive ChAd3-EBO-Z (day 0), or saline placebo (day 0) and ChAd3-EBO-Z (month 6). The study was observer-blind until planned interim day 30 analysis, single-blind until month 6, and open-label after month 6 vaccination. Primary outcomes assessed in the total vaccinated cohort, which comprised all participants with at least one study dose administration documented, were serious adverse events (up to study end, month 12); and for a subcohort were solicited local or general adverse events (7 days post-vaccination), unsolicited adverse events (30 days post-vaccination), haematological or biochemical abnormalities, and clinical symptoms of thrombocytopenia (day 0-6). Secondary endpoints (subcohort; per-protocol cohort) evaluated anti-glycoprotein Ebola virus antibody titres (ELISA) pre-vaccination and 30 days post-vaccination. This study is registered with ClinicalTrials.gov, NCT02485301. Between July 22, 2015, and Dec 10, 2015, 3030 adults were randomly assigned; 3013 were included in the total vaccinated cohort (1509 [50·1%] in the ChAd3-EBO-Z group and 1504 [49·9%] in the placebo/ChAd3-EBO-Z group), 17 were excluded because no vaccine was administered. The most common solicited injection site symptom was pain (356 [48%] of 748 in the ChAd3-EBO-Z group vs 57 [8%] of 751 in the placebo/ChAd3-EBO-Z group); the most common solicited general adverse event was headache (345 [46%] in the ChAd3-EBO-Z group vs 136 [18%] in the placebo/ChAd3-EBO-Z group). Unsolicited adverse events were reported by 123 (16%) of 749 in the ChAd3-EBO-Z group and 119 (16%) of 751 in the placebo/ChAd3-EBO-Z group. Serious adverse events were reported for 11 (1%) of 1509 adults in the ChAd3-EBO-Z group, and 18 (1%) of 1504 in the placebo/ChAd3-EBO-Z group; none were considered vaccination-related. No clinically meaningful thrombocytopenia was reported. At day 30, anti-glycoprotein Ebola virus antibody geometric mean concentration was 900 (95% CI 824-983) in the ChAd3-EBO-Z group. There were no treatment-related deaths. ChAd3-EBO-Z was immunogenic and well tolerated in adults. Our findings provide a strong basis for future development steps, which should concentrate on multivalent approaches (including Sudan and Marburg strains). Additionally, prime-boost approaches should be a focus with a ChAd3-based vaccine for priming and boosted by a modified vaccinia Ankara-based vaccine. EU's Horizon 2020 research and innovation programme and GlaxoSmithKline Biologicals SA.

Immunologic Dose-Response to Adenovirus-Vectored Vaccines in Animals and Humans: A Systematic Review of Dose-Response Studies of Replication Incompetent Adenoviral Vaccine Vectors when Given via an Intramuscular or Subcutaneous Route.

Optimal vaccine dosing is important to ensure the greatest protection and safety. Analysis of dose-response data, from previous studies, may inform future studies to determine the optimal dose. Implementing more quantitative modelling approaches in vaccine dose finding have been recently suggested to accelerate vaccine development. Adenoviral vectored vaccines are in advanced stage of development for a variety of prophylactic and therapeutic indications, however dose-response has not yet been systematically determined. To further inform adenoviral vectored vaccines dose identification, historical dose-response data should be systematically reviewed. A systematic literature review was conducted to collate and describe the available dose-response studies for adenovirus vectored vaccines. Of 2787 papers identified by Medline search strategy, 35 were found to conform to pre-defined criteria. The majority of studies were in mice or humans and studied adenovirus serotype 5. Dose-response data were available for 12 different immunological responses. The majority of papers evaluated three dose levels, only two evaluated more than five dose levels. The most common dosing range was 107–1010 viral particles in mouse studies and 108–1011 viral particles in human studies. Data were available on adenovirus vaccine dose-response, primarily on adenovirus serotype 5 backbones and in mice and humans. These data could be used for quantitative adenoviral vectored vaccine dose optimisation analysis.

Nash SIR: An Economic-Epidemiological Model of Strategic Behavior During a Viral Epidemic

This paper develops a Nash-equilibrium extension of the classic SIR model of infectious-disease epidemiology ("Nash SIR"), endogenizing people's decisions whether to engage in economic activity during a viral epidemic and allowing for complementarity in social-economic activity. An equilibrium epidemic is one in which Nash equilibrium behavior during the epidemic generates the epidemic. There may be multiple equilibrium epidemics, in which case the epidemic trajectory can be shaped through the coordination of expectations, in addition to other sorts of interventions such as stay-at-home orders and accelerated vaccine development. An algorithm is provided to compute all equilibrium epidemics.

Revisiting regulatory framework in India for accelerated vaccine development in pandemics with an evidence-based fast-tracking strategy.

Revisiting regulatory framework in India for accelerated vaccine development in pandemics with an evidence-based fast-tracking strategy.

Characterization of potential biomarkers of reactogenicity of licensed antiviral vaccines: randomized controlled clinical trials conducted by the BIOVACSAFE consortium

Biomarkers predictive of inflammatory events post-vaccination could accelerate vaccine development. Within the BIOVACSAFE framework, we conducted three identically designed, placebo-controlled inpatient/outpatient clinical studies (NCT01765413/NCT01771354/NCT01771367). Six antiviral vaccination strategies were evaluated to generate training data-sets of pre-/post-vaccination vital signs, blood changes and whole-blood gene transcripts, and to identify putative biomarkers of early inflammation/reactogenicity that could guide the design of subsequent focused confirmatory studies. Healthy adults (N = 123; 20–21/group) received one immunization at Day (D)0. Alum-adjuvanted hepatitis B vaccine elicited vital signs and inflammatory (CRP/innate cells) responses that were similar between primed/naive vaccinees, and low-level gene responses. MF59-adjuvanted trivalent influenza vaccine (ATIV) induced distinct physiological (temperature/heart rate/reactogenicity) response-patterns not seen with non-adjuvanted TIV or with the other vaccines. ATIV also elicited robust early (D1) activation of IFN-related genes (associated with serum IP-10 levels) and innate-cell-related genes, and changes in monocyte/neutrophil/lymphocyte counts, while TIV elicited similar but lower responses. Due to viral replication kinetics, innate gene activation by live yellow-fever or varicella-zoster virus (YFV/VZV) vaccines was more suspended, with early IFN-associated responses in naïve YFV-vaccine recipients but not in primed VZV-vaccine recipients. Inflammatory responses (physiological/serum markers, innate-signaling transcripts) are therefore a function of the vaccine type/composition and presence/absence of immune memory. The data reported here have guided the design of confirmatory Phase IV trials using ATIV to provide tools to identify inflammatory or reactogenicity biomarkers.

Factors influencing participation in controlled human infection models: a pooled analysis from six enteric fever studies

Background: Enteric fever is an acute febrile-illness caused by infection with the human-restricted Salmonella serovars Typhi and Paratyphi. Controlled human infection models (CHIM) of S. Typhi and Paratyphi infection are used to accelerate vaccine development and to better understand host-pathogen interactions. The primary motivations for participants to take part in these studies are unknown. We studied participant motivations, attitudes and the factors influencing CHIM study participation. Methods: Participant surveys were nested in six enteric fever CHIM studies conducted at a single centre in Oxford, UK, between 2011 and 2017. All eligible participants received one invitation to complete an anonymous, self-administered paper or online survey on either day 28 or 60 after challenge. A descriptive analysis was performed on these pooled data. All studies were included, to minimize selection bias. Results: Survey response rates varied from 33.0%-86.1%, yielding 201 participants. In the cohort, 113/198(57.0%) were educated to bachelor’s level, 61.6% were employed, 30.3% were students and 4.6% were unemployed. The most commonly cited motivations for CHIM study participation were a desire to contribute to the progression of medicine (170/201; 84.6%); the prospect of financial reimbursement (166/201; 82.6%) and curiosity about clinical trials (117/201; 57.2%). The majority of respondents (139/197; 70.6%) reported that most people advised them against participation. Conclusion: Motivation to participate in a CHIM study was multi-factorial and heavily influenced by internal drivers beyond monetary reimbursement alone. High educational attainment and employment may be protective factors against financial inducement; however, further research is needed, particularly with CHIM studies expanding to low-income and middle-income countries.

Risk assessment for the implementation of controlled human Schistosoma mansoni infection trials in Uganda.

Schistosomiasis is a parasitic infection highly prevalent in sub-Saharan Africa, and a significant cause of morbidity; it is a priority for vaccine development. A controlled human infection model for Schistosoma mansoni (CHI-S) with potential to accelerate vaccine development has been developed among naïve volunteers in the Netherlands. Because responses both to infections and candidate vaccines are likely to differ between endemic and non-endemic settings, we propose to establish a CHI-S in Uganda where Schistosoma mansoni is endemic. As part of a "road-map" to this goal, we have undertaken a risk assessment. We identified risks related to importing of laboratory vector snails and schistosome strains from the Netherlands to Uganda; exposure to natural infection in endemic settings concurrently with CHI-S studies, and unfamiliarity of the community with the nature, risks and rationale for CHI. Mitigating strategies are proposed. With careful implementation of the latter, we believe that CHI-S can be implemented safely in Uganda. Our reflections are presented here to promote feedback and discussion.

Human monoclonal antibodies for discovery, therapy, and vaccine acceleration.

Screening of single B cells from convalescent or vaccinated people allows the discovery of novel targets for infectious diseases and rapid production of engineered human monoclonal antibodies (mAbs) that can prevent or control infections by passive immunization. Here we propose that the development of human mAbs can also significantly accelerate vaccine development by anticipating some of the key biological and regulatory questions.