Clinical Vaccine Studies Research Articles

Assessment of antibodies against platelet factor 4 following vaccination with adenovirus type 26–vectored vaccines

BackgroundVaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse event identified following vaccination with some adenovirus-vectored COVID-19 vaccines, including Ad26.COV2.S. VITT is characterized by the presence of antibodies against platelet factor 4 (PF4). ObjectivesTo evaluate whether PF4 antibodies were generally induced following vaccination with adenovirus type 26 (Ad26)–vectored vaccines. MethodsThe study included 913 and 991 healthy participants without thromboembolic (TE) events in Ad26.COV2.S and non–COVID-19 Ad26-vectored vaccine clinical studies, respectively, and 1 participant with VITT following Ad26.COV2.S vaccination. PF4 antibody levels were measured in prevaccination and postvaccination sera. PF4 antibody positivity rates were assessed in a case-control setting in participants who developed TE events during participation in Ad26-vectored vaccine clinical studies. ResultsIn the 1 VITT patient, PF4 antibodies were negative before vaccination. Seroconversion for platelet-activating PF4 antibodies was observed upon Ad26.COV2.S vaccination. In participants without TE events, the PF4 antibody levels and positivity rates were similar before and after Ad26 vaccination. Ad26 vaccination did not increase PF4 antibody levels in participants who were PF4 antibody–positive at baseline (n = 47). Lastly, 1 out of 28 TE cases and 2 out of 156 non-TE controls seroconverted after Ad26.COV2.S vaccination. None of the 15 TE cases and 3 of the 77 non-TE controls seroconverted following non–COVID-19 Ad26 vaccination. ConclusionAd26.COV2.S and the other Ad26-vectored vaccines studied did not generally induce PF4 antibodies or increase preexisting PF4 antibody levels. Moreover, unlike VITT, TE events that occurred at any time following Ad26 vaccination were not associated with PF4 antibodies.

Fully closed and automated enrichment of primary blood dendritic cells for cancer immunotherapy.

Dendritic cell (DC) vaccination is a promising approach to induce tumor-specific immune responses in cancer patients. Until recently, most DC vaccines were based on in vitro-differentiated monocyte-derived DCs. However, through development of efficient isolation techniques, the use of primary blood dendritic cell subsets has come within reach. Manufacturing of blood-derived DCs has multiple advances over monocytes-derived DCs, including more standardized isolation and culture protocols and shorter production processes. In peripheral blood, multiple DC subsets can be distinguished based on their phenotype and function. Plasmacytoid DC (pDC) and myeloid/conventional DCs (cDC) are the two main DC populations, moreover cDC can be further subdivided into CD141/BDCA3+ DC (cDC1) and CD1c/BDCA1+ DC (cDC2). In three separate clinical DC vaccination studies in melanoma and prostate cancer patients, we manufactured DC vaccines consisting of pDCs only, cDC2s only, or a combination of pDC and cDC2s, which we called natural DCs (nDC). Here, we describe a fully closed and automated GMP-compliant method to enrich naturally circulating DCs and present the results of enrichment of primary blood DCs from aphaeresis products of 8 healthy donors, 21 castrate-resistant prostate cancer patients, and 112 stage III melanoma patients. Although primary blood DCs are relatively scarce in aphaeresis material, our results show that it is feasible to isolate highly pure pDC, cDC2, or nDC with sufficient yield to manufacture DC vaccines for natural DC-based immunotherapy.

MRNA vaccines in the rheumatologist's future

BackgroundVaccines taking advantage of mRNA technology have been long in development. ObjectivesTo review the status of approved mRNA vaccines for infectious diseases as well as those in development. MethodsSystematic literature review of clinical and immunologic studies of mRNA vaccines against infectious diseases. ResultsCurrently approved mRNA vaccines include those against SARS CoV-2 virus. They are immunogenic and provide good protection against severe disease. A number of mRNA vaccines for influenza are in development including in phase 3 studies. Other such vaccines in development include those targeting Epstein-Barr Virus (EBV), Cytomegalovirus (CMV), varicella (VZV), and respiratory syncytial virus (RSV). Many of these vaccines will likely be indicated for immunosuppressed populations including those with autoimmune inflammatory diseases. ConclusionsA number of mRNA vaccines against viral pathogens are in early to late phase development. The ability to rapidly change vaccine constituents and target complex targets, make mRNA vaccines likely to be adopted in the future.

Molecular detection of pre-ribosomal RNAs of Mycobacterium bovis bacille Calmette-Guérin and Mycobacterium tuberculosis to enhance pre-clinical tuberculosis drug and vaccine development

Efforts are underway globally to develop effective vaccines and drugs against M. tuberculosis (Mtb) to reduce the morbidity and mortality of tuberculosis. Improving detection of slow-growing mycobacteria could simplify and accelerate efficacy studies of vaccines and drugs in animal models and human clinical trials. Here, a real-time reverse transcription PCR (RT-PCR) assay was developed to detect pre-ribosomal RNA (pre-rRNA) of Mycobacterium bovis bacille Calmette-Guérin (BCG) and Mtb. This pre-rRNA biomarker is indicative of bacterial viability. In two different mouse models, the presence of pre-rRNA from BCG and Mtb in ex vivo tissues showed excellent agreement with slower culture-based colony-forming unit assays. The addition of a brief nutritional stimulation prior to molecular viability testing further differentiated viable but dormant mycobacteria from dead mycobacteria. This research has set the stage to evaluate pre-rRNA as a BCG and/or Mtb infection biomarker in future drug and vaccine clinical studies.

Adjuvant polypeptide vaccines for high-risk uveal melanoma.

e21509 Background: Due to biologic differences, uveal melanoma patients are often excluded from clinical trials for cutaneous melanoma; however, many antigens are shared between the two melanoma subtypes. Thus, our vaccine trials at the University of Virginia (UVA) have allowed enrollment of high-risk uveal melanoma patients, who have substantial risk of relapse without FDA-approved adjuvant therapy available. For the present study, we hypothesized that the vaccines would be well-tolerated and immunogenic in this population. We examined the clinical, immunogenicity and safety outcomes of subjects with uveal melanoma enrolled in our adjuvant vaccine clinical studies. Methods: Patients were identified through participation in an adjuvant vaccine study at UVA between 2012-2022. Ten patients received the 6-Melanoma-Helper Peptide (6-MHP) vaccine through Mel-65 and Mel-66 clinical trials (NCT03617328 and NCT04364230) and one patient received the 12-peptide MELITAC vaccine through the Mel-58 clinical trial (NCT01585350). Clinical outcomes included relapse-free (RFS) and overall survival (OS) and trial toxicity reporting. Immunogenicity was assessed by ex vivo interferon-gamma ELISpot assay of peripheral T cells. OS and RFS were reported by Kaplan-Meier survival analysis and compared by log rank test between groups. Results: Of the 11 identified patients, nine were male (82%) and two were female (18%), with a median age of 64 years. All patients were high risk by molecular testing, the majority by Castle Bioscience DecisionDx-UM. Five were PRAME positive, five PRAME negative, and one not reported. In the cohort, three patients had uveal melanoma recurrence and one subject died from metastatic disease during the evaluation period. The 5-year RFS and OS were 71% (95% CI 43-100) and 80% (95% CI 52-100), respectively. Two patients experienced dose-limiting, grade 3 toxicities to the vaccine, requiring early trial discontinuation, including one grade 3 injection-site reaction and one grade 3 uveitis. Nine patients experienced grade 1-2 toxicities, mostly injection-site reactions and constitutional symptoms. Of nine patients with available immunogenicity data, five (55%) had direct antigen-mediated immune response to vaccine. Two patients’ responses are pending. Patients with immunogenic response had a non-significant trend toward better RFS and OS (both p = 0.22). The 3-year RFS and OS were 100% for subjects with T cell response and the RFS and OS were 50% (95% CI 13-100) for patients without T cell response. Two of the relapsed patients did not have an immune response to vaccine, and response data were not available for the third. Conclusions: Melanoma polypeptide vaccines are immunogenic and safe in patients with uveal melanoma. Our early data suggests the possibility of early benefit with direct antigen response, though longer follow up and further study will be needed to investigate these findings.

Current approaches to quality assessment, non-clinical and clinical studies of dendritic cell vaccines in oncology

At present, personalised cellular immunotherapy is considered a promising approach to the treatment of malignant neoplasms. The effectiveness of these cellular immunotherapy methods is evaluated in the context of clinical and biological tumour characteristics and the state of the immune system of a particular patient. One of the immunotherapy options for cancer is the development of autologous dendritic cell vaccines.The aim of this study was to analyse current methodological approaches to the evaluation of the quality, efficacy, and safety of dendritic cell cancer vaccines.This review describes the functional role of dendritic cells in immune response regulation. The paper presents the results of literature analysis covering current approaches to obtaining dendritic cell vaccines with specific characteristics, quality assessment, studies of the anti-tumour efficacy of cell therapy products, and the experience of conducting non-clinical and clinical studies. The review highlights specific aspects of international experience in the registration and clinical use of cell therapy products. The authors discuss methodological approaches to non-clinical studies of dendritic cell vaccines, which should aim to obtain information to select the dose, route, and mode of administration and to identify immunological markers correlating to the clinical efficacy of cell therapy products. The paper covers international experience in conducting clinical trials of dendritic cell vaccines for various malignant neoplasms. The authors propose a list of quality attributes of human somatic cell-based medicinal products for further clinical use.

Evaluation of Side Effects Associated with COVID-19 Vaccines in Pregnant Women.

A variety of vaccinations have been developed to fight the coronavirus disease 2019 (Covid-19) 2 years after the coronavirus epidemic spread globally. During clinical studies, these vaccinations were linked to mild to severe side effects. This study aimed to evaluate the short-term side effects of Covid-19 vaccination in pregnant women in Zabol (Iran). This cross-sectional study was conducted between August and October 2021 to collect data on the adverse side effects of Covid-19 vaccinations among 117 pregnant women in Zabol (Iran). A questionnaire was used to collect demographic data, vaccination information, and vaccine complications. SPSS software Version 22 was used to analyze the data at 2 levels descriptive and inferential statistics. A total of 117 pregnant women aged 27.67 ± 5.14 years were included. After the first and second doses of Covid-19 vaccinations, 91 (86.7%) and 84 (71.8%) pregnant women, respectively, suffered adverse effects. Moreover, after the first dose, 55(51.4%) and 60 (56.1%) of pregnant women reported fatigue and headache, and after the second dose, 39 (33.3%) and 37 (31.6%) reported fatigue and headache, respectively. The side effects reported in our study after receiving Covid-19 vaccinations in pregnant women were similar to those described in clinical studies of vaccines and were mild to moderate, showing that injectable vaccines had safe profiles. More research is needed, however, to assess the long-term side effects of existing vaccines.

IL-4 Predicts the Efficacy of a Candidate Antioxycodone Vaccine and Alters Vaccine-Specific Antibody-Secreting Cell Proliferation in Mice.

Opioid use disorders (OUDs) are a public health concern in the United States and worldwide. Current medications for OUDs may trigger side effects and are often heavily regulated. A novel treatment strategy to be used alone or in combination with existing medications is active immunization with antiopioid vaccines, which stimulate production of opioid-specific Abs that bind to the target drug and prevent its distribution to the brain. Although antiopioid vaccines have shown promising preclinical efficacy, prior clinical evaluations of vaccines targeting stimulants indicate that efficacy is limited to a subset of subjects who achieve optimal Ab responses. We have previously reported that depletion of IL-4 with a mAb increased opioid-specific IgG2a and total IgG, and it increased the number of germinal centers and germinal center T follicular helper cells in response to antiopioid vaccines via type I IL-4 signaling. The current study further investigates the mechanisms associated with IL-4-mediated increases in efficacy and whether IL-4 depletion affects specific processes involved in germinal center formation, including affinity maturation, class switching, and plasma cell differentiation in mice. Additionally, results demonstrate that preimmunization production of IL-4 after ex vivo whole blood stimulation predicted invivo vaccine-induced Ab titers in outbred mice. Such mechanistic studies are critical for rational design of next-generation vaccine formulations, and they support the use of IL-4 as a predictive biomarker in ongoing OUD vaccine clinical studies.

Peptide antitumor vaccines targeting HER2/neu

Antitumor vaccines are aimed at correcting cellular immunity by overcoming immunological tolerance with eluding surveillance due to the specific presentation of tumor-associated or tumor-specific antigens to immunocompetent cells.The purpose of this review was to study modern strategies for the development of antitumor vaccines containing epitopes of HER2/neu receptors acting as tumor-associated antigens. Approaches to the creation of such vaccines are classified by targeting the T-cell link or B-cells by the choice and length of the epitopes used or by the use of specific adjuvants.The review provides information on this topic, obtained from more than 50 publications of the last 20 years, found in the most significant sources of citation. The text is categorized for the convenience of perception by scientists of different specialties and is completed with a brief conclusion with an emphasis on development prospects. The results of clinical studies of vaccines with an analysis of the immunological features of the results of immunotherapy, mainly breast cancer with HER2/neu expression, are considered. Vaccines targeting different histocompatibility complexes are compared. The review traces the evolution of vaccine preparations from the simplest containing short peptide sequences to complex combined systems, including viral vectors. Attention is paid to various methodological approaches used in the development of such drugs: from computer design and phage display in experiments in vitro/in vivo. The emphasis is placed on the problem of a personalized approach to vaccination of an oncological patient associated with a mutation process occurring inside tumors and leading to the appearance of unique tumor-associated antigens. The participation of complement system components in antibody-mediated lysis of tumor cells induced by the presented vaccines is discussed.Thus, the review introduces readers to the existing directions of creating immune drugs designed to suppress the development of the tumor process by activating the body’s own immune forces and the prospect of their development.

Advances in clinical research of virus vector-based COVID-19 vaccines

The COVID-19 outbreak at the end of 2019 has accelerated the development and research for COVID-19 vaccines worldwide. Among the COVID-19 vaccines in clinical trials developed via different platforms, recombinant virus vector-based vaccines have shown excellent immunogenicity and efficacy. However, at the same time, there are serious issues such as vaccine safety and pre-existing antibodies against vectors. This article summarizes the design concept and development history of recombinant virus vector-based vaccines, and focuses on the progress in the clinical studies of vector-based COVID-19 vaccines as well as the challenges, in order to provide reference for the research of recombinant vector-based vaccines.

Promising opportunities to improve polio vaccines

Polioviruses belong to Enterovirus C species and cause severe lesions of the nervous system. In the post-polio eradication era, the World Health Organisation recommends inactivated polio vaccines for effective long-term protection of the population. In order to meet the needs of global health, it is planned to increase the use of traditional and optimised inactivated polio vaccines and introduce new types of vaccines that are being developed based on the current understanding of RNA-containing viruses. The aim of the study was to analyse ways of improving vaccine preparations and to review promising areas for polio immunoprophylaxis development. The authors considered innovations across all stages of the technological process, aimed at obtaining optimised vaccines, as well as vaccine delivery systems. The article presents information on new vaccine strains and cell lines for vaccine production. The authors summarised the results of clinical studies of inactivated vaccines, new vaccines based on genetically stable vaccine strains of poliovirus, and vaccines containing virus-like particles. The most likely candidates for introduction are the vaccines based on virus-like particles obtained from genetically modified strains of poliovirus. At the moment, many issues related to current trends in improving the immunoprophylaxis of poliomyelitis are debatable and need to be addressed in the near future.

HPR36 Using Best-Worst Scaling to Identify the Important Barriers to COVID-19 Vaccination in Black Belt Region: A Pilot Study

HPR36 Using Best-Worst Scaling to Identify the Important Barriers to COVID-19 Vaccination in Black Belt Region: A Pilot Study

Managing multiplicity in clinical vaccine studies – A case study using a gatekeeping testing strategy

BackgroundMultiplicity issues are increasingly common in vaccine clinical studies. Common causes include multi-valent combinations/co-administrations requiring separate evaluation of each antigen; numerous efficacy endpoints; requests from regulatory authorities for inclusion of specific powered endpoints into registration studies; interim analyses to support early decision-making. In a Phase III study to evaluate safety and immunogenicity of the 4-component Neisseria meningitidis serogroup B vaccine (4CMenB) when co-administered with 13-valent pneumococcal conjugate vaccine (PCV13) to healthy infants, a total of 49 statistical hypotheses were identified for the primary objectives as requested by the health authority. We designed a sequential testing strategy with visualization using a graphical gatekeeping procedure. MethodsThe 49 immunogenicity objectives related to evaluation of the sufficiency of the 4CMenB immune response; and demonstration of non-inferiority of PCV13 and 4CMenB when co-administered versus administration alone. We used a graphical shortcut display for closed families assuming that the multiple testing procedure is consonant and hypotheses that are rejected by a closed testing procedure are also rejected within the graphical short-cut. The 49 hypotheses were grouped into 10 families and distributed over 4 sequential steps following the clinical and statistical logical relationships agreed with the clinical team. Test decisions within the first 8 families will be made based on p-values with alpha propagation to subsequent families according to the tree structure. ResultsThis tailored strategy allowed evaluation of all 49 statistical hypotheses individually, and more efficiently. The method avoided a rigid all-or-nothing approach whereby all endpoints fail if one or more null hypotheses cannot be rejected. Clinical input and agreement are critical for designing an efficient and fit-for-purpose strategy. Our experience could encourage more application of such strategies in increasingly complex clinical trials.

On the Twentieth Anniversary of Dendritic Cell Vaccines - Riding the Next Wave.

In the mid 1990's, a convergence of discoveries in dendritic cell (DC) biology and tumor antigen identification led investigators to study DCs as adjuvants for cancer vaccines. On the twentieth anniversary of a seminal clinical study by Jacques Banchereau and colleagues, we revisit the key events that prompted the initial wave of DC vaccine clinical studies and lessons learned that, in our opinion, helped forge the path for the field that we now call immuno-oncology. It is essential to recall that prior to the discovery of immune checkpoint therapy and chimeric antigen receptor (CAR) T-cell therapy, skepticism prevailed regarding the potential therapeutic benefit of immunotherapies. In hindsight, we can now appreciate how the early DC cancer vaccine trials helped investigators sustain their attention on adaptive immunity specific for malignant cells. These vaccines demonstrated clear evidence for induction of antigen-specific T cells and were well tolerated despite low rates of objective clinical response. In the context of the current era some 20 years later, harnessing DC vaccines has been shown to increase the breadth and diversity of tumor-specific T cells, and by trafficking to sites of metastases promote an inflamed tumor microenvironment. See related article by Banchereau and colleagues, Cancer Res 2001; 61:6451-8.

Challenges of COVID-19 vaccination in patients with cancer

Patients with cancer are at increased risk of SARA-CoV-2 infection or developing severe COVID-19 cases due to the malignancy or immunosuppressive therapy, but they are generally excluded from the target population for COVID-19 vaccination. In general, inactivated vaccines are safe and immunogenic for patients with cancer, but live attenuated vaccines are not recommended. The study suggested that the safety of the mRNA COVID-19 vaccine in cancer patients is similar to that in healthy people, but the immunogenicity is slightly weaker, and a booster dose may be needed. This paper aims to summarize the results of COVID-19 vaccine clinical studies conducted in cancer patients worldwide and the relevant guidelines released by authorities, so as to provide evidence for promoting COVID-19 vaccination for cancer patients.

Effectiveness and Efficacy of Vaccine on Mutated SARS-CoV-2 Virus and Post Vaccination Surveillance: A Narrative Review.

The ongoing COVID-19 pandemic, as a result of the SARS-CoV-2 virus, since December 2019, is a major health problem and concern worldwide. The pandemic has impacted various fields, from the social to the development of health science and technology. The virus has been mutating and thus producing several new variants, rushing research in the field of molecular biology to develop rapidly to overcome the problems that occur. Vaccine clinical studies are developing promptly with the aim of obtaining vaccines that are effective in suppressing the spread of the virus; however, the development of viral mutations raises concerns about the decreasing effectiveness of the resulting vaccine, which also results in the need for more in-depth studies. There have been 330 vaccines developed, including 136 clinical developments and 194 pre-clinical developments. The SARS-CoV-2 variant continues to evolve today, and it poses a challenge in testing the effectiveness of existing vaccines. This is a narrative review describing the emergence of the COVID-19 pandemic, development of vaccine platforms, identification of concerning mutations and virus variants in various countries of the world, and real-world monitoring of post-vaccination effectiveness and surveillance.

SARS-CoV-2 vaccination in patients with inflammatory bowel disease: A systemic review and meta-analysis.

In the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination has been effective in preventing COVID-19 infections and related mortality. The SARS-CoV-2 vaccination was also recommended by the international society for patients with inflammatory bowel disease (IBD). However, IBD patients were not recruited in prospective randomized clinical vaccine studies. To evaluate the efficacy and safety of SARS-CoV-2 vaccination in IBD patients, we conducted this systemic review and meta-analysis. We systematically searched PubMed, Medline, and the Cochrane Library for studies published between January 1, 2019, and September 9, 2021. Studies written in English reported the efficacy, seroconversion (anti-SARS-CoV-2 anti-spike (S) antibody titer beyond the threshold) rate, and adverse events after the SARS-CoV-2 vaccination in IBD patients. We extracted the author, date, study design, country, types of SARS-CoV-2 vaccination, number of IBD patients receiving SARS-CoV-2 vaccinations, and study outcomes. Published data from the enrolled studies were pooled to determine effect estimates. The study protocol was registered in PROSPERO (CRD42021264993). We analyzed findings from 27 454 IBD patients who received SARS-CoV-2 vaccinations in 11 studies that met the inclusion criteria. The post-SARS-CoV-2 vaccination COVID-19 infection rate was comparable between the IBD patients and non-IBD patients (odds ratio [OR], 1.28 [95% CI, 0.96-1.71]) and higher in nonvaccinated IBD patients compared with vaccinated IBD patients (OR, 8.63 [95% CI, 5.44-13.37]). The adverse event rate, severe adverse events, and mortality after the SARS-CoV-2 vaccination were 69%, 3%, and 0%, respectively. The SARS-CoV-2 vaccine is effective and tolerated in preventing COVID-19 infections in IBD patients. Over 98% of patients had seroconversion after receiving all doses of the SARS-CoV-2 vaccination, and the influence of biologics on vaccination was limited. The SARS-CoV-2 vaccination is recommended for IBD patients.

Vaccines for gastrointestinal parasites, a pillar of preventive medicine in veterinary practice: Systematic review

Contextualization: The antiparasitic resistance caused by the indiscriminate use of anthelmintic drugs for the control of gastrointestinal parasites in production animals and pets, has become one of the biggest problems in animal health. For this reason, the use of vaccines could benefit animal health and welfare by controlling emerging zoonotic diseases and foodborne pathogens of animal origin, thus improving public health. Knowledge gap: It is relevant for professionals in veterinary science to know the clinical trials of experimental vaccines for controlling certain gastrointestinal parasites. This way, they can be at the forefront of the next available technological products and so, be able to control this menace to the animal health and public health. Purpose: To do a systematic review of clinical trials for experimental vaccines in production animals and pets for diseases caused by gastrointestinal parasites of relevance in animal production and/or public health. Furthermore, it presents the current gastrointestinal antiparasitic vaccines commercialized in different countries and their prophylactic efficacy. Methodology: PRISMA protocols were followed for this systematic review. Articles were obtained from scientific databases with the following keywords: vaccines, clinical trials, commercial vaccines, parasites control, gastrointestinal nematodes, gastrointestinal cestodes, gastrointestinal protozoa, Ascaris suum, Ancylostoma caninum, Cooperia oncophora, Echinococcus granulosus, Eimeria spp., Giardia lamblia, Haemonchus contortus, Osteortagia osteortagi, Taenia solium and Teladorsagia circumcincta. Only clinical trials of gastrointestinal antiparasitic vaccines in birds, pets, pigs and ruminants were included in this analysis, as well as commercial vaccines currently available for these same parasites. Results and conclusions: Even though there are important clinical trial studies of vaccines in these animal species (n=101) reported between 1964 to 2020, only five parasites can be prevented/controlled with commercial vaccines used in veterinary medicine: Haemonchus contortus and Echinococcus granulosus in ruminants, Taenia solium in pigs, Eimeria spp. in birds and Giardia lamblia in dogs (e.g., Cysvax™, Barbervax®, Providean® Hidatil EG95, CocciVac® and GiardiaVax™). It is expected that, with the development of bioinformatics and methodologies such as reverse vaccinology, this immunoprophylactic and immunotherapeutic range will be extended as to control these parasitic agents of great importance in human and animal health.

Sequence and vector shapes vaccine induced antibody effector functions in HIV vaccine trials

Despite the advent of long-acting anti-retroviral therapy able to control and prevent infection, a preventative vaccine remains a global priority for the elimination of HIV. The moderately protective RV144 vaccine trial suggested functional IgG1 and IgG3 antibodies were a potential correlate of protection, but the RV144-inspired HVTN702 validation trial failed to demonstrate efficacy despite inducing targeted levels of IgG1/IgG3. Alterations in inserts, and antigens, adjuvant, and regimen also resulted in vaccine induced target quantitative levels of the immune correlates, but drove qualitative changes to the humoral immune response, pointing to the urgent need to define the influence of vaccine strategies on shaping antibody quality, not just quantity. Thus, defining how distinct prime/boost approaches tune long-lived functional antibodies represents an important goal in vaccine development. Here, we compared vaccine responses in Phase I and II studies in humans utilizing various combinations of DNA/vector, vector/vector and DNA/protein HIV vaccines. We found that adenoviral vector immunization, compared to pox-viral vectors, resulted in the most potent IgG1 and IgG3 responses, linked to highly functional antibody activity, including assisting NK cell related functions. Minimal differences were observed in the durability of the functional humoral immune response across vaccine regimens, except for antibody dependent phagocytic function, which persisted for longer periods in the DNA/rAd5 and rAd35/rAd5 regimen, likely driven by higher IgG1 levels. Collectively, these findings suggest adenoviral vectors drive superior antibody quality and durability that could inform future clinical vaccine studies.Trial registration: ClinicalTrials.gov NCT00801697, NCT00961883, NCT02207920, NCT00125970, NCT02852005).

Approaches to quality control, preclinical and clinical studies of live recombinant viral vector vaccines

At present, there are not much data on the clinical use of live recombinant viral vector vaccines. Characteristics of new vaccines should be factored into requirements/recommendations for quality control, preclinical and clinical studies of vaccines in order to enable further risk/benefit assessment. The aim of this study was to analyse current approaches to quality control, preclinical and clinical studies of live recombinant viral vector vaccines. The paper provides an overview of the licensed live viral vector vaccines and those at various stages of clinical trials. The authors analysed Russian, European, American, and Japanese guidelines related to quality issues, preclinical and clinical studies of live viral vector vaccines. The analysis demonstrated that the regulatory requirements for live recombinant viral vector vaccines include assessment of a detailed rationale for vaccine development, including information on the choice of the vector, the origin of the heterologous antigen gene(s), elements related to the transgene(s) expression, as well as assessment of the genetic and phenotypic stability of the recombinant virus, the risk of reversion to virulence or recombination with wild type strains, the potential for virus genome integration into the host cell chromosome, the pre-existing immunity to the vector, the intensity of the immune response elicited by the vector, and the reusability of the vector. The choice and number of applicable toxicological and pharmacological models will depend on these aspects. The results of the analysis of approaches to quality control, preclinical and clinical studies of live recombinant viral vector vaccines may be used in the development of Russian regulatory guidelines harmonised with the international norms and regulations.