Effective Vaccine Candidate Research Articles

Efficacy of a low-dose candidate malaria vaccine, R21 in adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: a randomised controlled trial

SummaryBackgroundStalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 56% efficacy over 12 months in African children. We therefore assessed a new candidate vaccine for safety and efficacy.MethodsIn this double-blind, randomised, controlled, phase 2b trial, the low-dose circumsporozoite protein-based vaccine R21, with two different doses of adjuvant Matrix-M (MM), was given to children aged 5–17 months in Nanoro, Burkina Faso—a highly seasonal malaria transmission setting. Three vaccinations were administered at 4-week intervals before the malaria season, with a fourth dose 1 year later. All vaccines were administered intramuscularly into the thigh. Group 1 received 5 μg R21 plus 25 μg MM, group 2 received 5 μg R21 plus 50 μg MM, and group 3, the control group, received rabies vaccinations. Children were randomly assigned (1:1:1) to groups 1–3. An independent statistician generated a random allocation list, using block randomisation with variable block sizes, which was used to assign participants. Participants, their families, and the local study team were all masked to group allocation. Only the pharmacists preparing the vaccine were unmasked to group allocation. Vaccine safety, immunogenicity, and efficacy were evaluated over 1 year. The primary objective assessed protective efficacy of R21 plus MM (R21/MM) from 14 days after the third vaccination to 6 months. Primary analyses of vaccine efficacy were based on a modified intention-to-treat population, which included all participants who received three vaccinations, allowing for inclusion of participants who received the wrong vaccine at any timepoint. This trial is registered with ClinicalTrials.gov, NCT03896724.FindingsFrom May 7 to June 13, 2019, 498 children aged 5–17 months were screened, and 48 were excluded. 450 children were enrolled and received at least one vaccination. 150 children were allocated to group 1, 150 children were allocated to group 2, and 150 children were allocated to group 3. The final vaccination of the primary series was administered on Aug 7, 2019. R21/MM had a favourable safety profile and was well tolerated. The majority of adverse events were mild, with the most common event being fever. None of the seven serious adverse events were attributed to the vaccine. At the 6-month primary efficacy analysis, 43 (29%) of 146 participants in group 1, 38 (26%) of 146 participants in group 2, and 105 (71%) of 147 participants in group 3 developed clinical malaria. Vaccine efficacy was 74% (95% CI 63–82) in group 1 and 77% (67–84) in group 2 at 6 months. At 1 year, vaccine efficacy remained high, at 77% (67–84) in group 1. Participants vaccinated with R21/MM showed high titres of malaria-specific anti-Asn-Ala-Asn-Pro (NANP) antibodies 28 days after the third vaccination, which were almost doubled with the higher adjuvant dose. Titres waned but were boosted to levels similar to peak titres after the primary series of vaccinations after a fourth dose administered 1 year later.InterpretationR21/MM appears safe and very immunogenic in African children, and shows promising high-level efficacy.FundingThe European & Developing Countries Clinical Trials Partnership, Wellcome Trust, and National Institute for Health Research Oxford Biomedical Research Centre.

Compounds Identified from Marine Mangrove Plant (Avicennia alba) as Potential Antiviral Drug Candidates Against WDSV, an In-Silico Approach.

Walleye dermal sarcoma virus (WDSV) is a type of retrovirus, which affects most of the adult walleye fishes during the spawning time. The virus causes multiple epithelial tumors on the fish’s skin and fins that are liable for more than 50% of the mortality rate of fish around the world. Till now, no effective antiviral drug or vaccine candidates have been developed that can block the progression of the disease caused by the pathogen. It was found that the 582-amino-acid (aa) residues long internal structural gag polyprotein of the virus plays an important role in virus budding and virion maturation outside of the cell. Inhibition of the protein can block the budding and virion maturation process and can be developed as an antiviral drug candidate against the virus. Therefore, the study aimed to identify potential natural antiviral drug candidates from the tropical mangrove marine plant Avicennia alba, which will be able to block the budding and virion maturation process by inhibiting the activity of the gag protein of the virus. Initially, a homology modeling approach was applied to identify the 3D structure, followed by refinement and validation of the protein. The refined protein structures were then utilized for molecular docking simulation. Eleven phytochemical compounds have been isolated from the marine plant and docked against the virus gag polyprotein. Three compounds, namely Friedlein (CID244297), Phytosterols (CID12303662), and 1-Triacontanol (CID68972) have been selected based on their docking score −8.5 kcal/mol, −8.0 kcal/mol and −7.9 kcal/mol, respectively, and were evaluated through ADME (Absorption, Distribution, Metabolism and Excretion), and toxicity properties. Finally, molecular dynamics (MD) simulation was applied to confirm the binding stability of the protein-ligands complex structure. The ADME and toxicity analysis reveal the efficacy and non-toxic properties of the compounds, where MD simulation confirmed the binding stability of the selected three compounds with the targeted protein. This computational study revealed the virtuous value of the selected three compounds against the targeted gag polyprotein and will be effective and promising antiviral candidates against the pathogen in a significant and worthwhile manner. Although in vitro and in vivo study is required for further evaluation of the compounds against the targeted protein.

Genome-wide screening of vaccine targets prioritization and reverse vaccinology aided design of peptides vaccine to enforce humoral immune response against Campylobacter jejuni

Campylobacter jejuni, gram-negative bacteria, is an infectious agent of foodborne disease-causing bloody diarrhea, abdominal pain, fever, Guillain-Barré syndrome (GBS) and Miller Fisher syndrome in humans. Campylobacter spp. with multidrug resistance to fluoroquinolones, tetracycline, and erythromycin are reported. Hence, an effective vaccine candidate would provide long-term immunity against C. jejuni infections. Thus, we used a subtractive proteomics pipeline to prioritize essential proteins, which impart a critical role in virulence, replication and survival. Five proteins, i.e. Single-stranded DNA-binding protein, UPF0324 membrane protein Cj0999c, DNA translocase FtsK, 50S ribosomal protein L22, and 50S ribosomal protein L1 were identified as virulent proteins and selected for vaccine designing. We reported that the multi-epitopes subunit vaccine based on CTL, HTL and B-cell epitopes combination possess strong antigenic properties and associates no allergenic reaction. Further investigation revealed that the vaccine interacts with the immune receptor (TLR-4) and triggered the release of primary and secondary immune factors. Moreover, the CAI and GC contents obtained through codon optimization were reported to be 0.93 and 53% that confirmed a high expression in the selected vector. The vaccine designed in this study needs further scientific consensus and will aid in managing C. jejuni infections.

COVID-19 Vaccines: Current Understanding on Immunogenicity, Safety, and Further Considerations.

The world has entered the second wave of the COVID-19 pandemic, and its intensity is significantly higher than that of the first wave of early 2020. Many countries or regions have been forced to start the second round of lockdowns. To respond rapidly to this global pandemic, dozens of COVID-19 vaccine candidates have been developed and many are undergoing clinical testing. Evaluating and defining effective vaccine candidates for human use is crucial for prioritizing vaccination programs against COVID-19. In this review, we have summarized and analyzed the efficacy, immunogenicity and safety data from clinical reports on different COVID-19 vaccines. We discuss the various guidelines laid out for the development of vaccines and the importance of biological standards for comparing the performance of vaccines. Lastly, we highlight the key remaining challenges, possible strategies for addressing them and the expected improvements in the next generation of COVID-19 vaccines.

SARS-CoV-2 population-based seroprevalence studies in Europe: a scoping review

ObjectivesWe aimed to review SARS-CoV-2 seroprevalence studies conducted in Europe to understand how they may be used to inform ongoing control strategies for COVID-19.DesignScoping review of peer-reviewed publications and manuscripts...

A Whole Virion Vaccine for COVID-19 Produced via a Novel Inactivation Method and Preliminary Demonstration of Efficacy in an Animal Challenge Model

The COVID-19 pandemic has generated intense interest in the rapid development and evaluation of vaccine candidates for this disease and other emerging diseases. Several novel methods for preparing vaccine candidates are currently undergoing clinical evaluation in response to the urgent need to prevent the spread of COVID-19. In many cases, these methods rely on new approaches for vaccine production and immune stimulation. We report on the use of a novel method (SolaVAX) for production of an inactivated vaccine candidate and the testing of that candidate in a hamster animal model for its ability to prevent infection upon challenge with SARS-CoV-2 virus. The studies employed in this work included an evaluation of the levels of neutralizing antibody produced post-vaccination, levels of specific antibody sub-types to RBD and spike protein that were generated, evaluation of viral shedding post-challenge, flow cytometric and single cell sequencing data on cellular fractions and histopathological evaluation of tissues post-challenge. The results from this preliminary evaluation provide insight into the immunological responses occurring as a result of vaccination with the proposed vaccine candidate and the impact that adjuvant formulations, specifically developed to promote Th1 type immune responses, have on vaccine efficacy and protection against infection following challenge with live SARS-CoV-2. This data may have utility in the development of effective vaccine candidates broadly. Furthermore, the results of this preliminary evaluation suggest that preparation of a whole virion vaccine for COVID-19 using this specific photochemical method may have potential utility in the preparation of one such vaccine candidate.

A murine model of tuberculosis/type 2 diabetes comorbidity for investigating the microbiome, metabolome and associated immune parameters.

Tuberculosis (TB) is one of the deadliest infectious diseases in the world. The metabolic disease type 2 diabetes (T2D) significantly increases the risk of developing active TB. Effective new TB vaccine candidates and novel therapeutic interventions are required to meet the challenges of global TB eradication. Recent evidence suggests that the microbiota plays a significant role in how the host responds to infection, injury and neoplastic changes. Animal models that closely reflect human physiology are crucial in assessing new treatments and to decipher the underlying immunological defects responsible for increased TB susceptibility in comorbid patients. In this study, using a diet‐induced murine T2D model that reflects the etiopathogenesis of clinical T2D and increased TB susceptibility, we investigated how the intestinal microbiota may impact the development of T2D, and how the gut microbial composition changes following a very low‐dose aerosol infection with Mycobacterium tuberculosis (Mtb). Our data revealed a substantial intestinal microbiota dysbiosis in T2D mice compared to non‐diabetic animals. The observed differences were comparable to previous clinical reports in TB patients, in which it was shown that Mtb infection causes rapid loss of microbial diversity. Furthermore, diversity index and principle component analyses demonstrated distinct clustering of Mtb‐infected non‐diabetic mice vs. Mtb‐infected T2D mice. Our findings support a broad applicability of T2D mice as a tractable small animal model for studying distinct immune parameters, microbiota and the immune‐metabolome of TB/T2D comorbidity. This model may also enable answers to be found to critical outstanding questions about targeted interventions of the gut microbiota and the gut‐lung axis.

A matter of priority: equitable access to COVID-19 vaccines.

Over past months, several effective COVID-19 vaccine candidates have been developed in different countries around the world, with some of them still being in the approval phase. At the same time, the impossibility of having enough vaccines for everyone in the near future has opened the floor for a debate about the priority of values and ethical principles that should guide vaccine allocation. There are, most notably, two main opposing ideas, with several views in between. Some argue that vaccines should be allocated equitably at the global level, and others claim that it is right and proper for governments to prioritise populations at the national level. What we currently see is that some high-income countries (HICs) have launched massive COVID-19 vaccination campaigns, whereas many low- and middle-income countries (LMICs) will have to wait considerably before immunisation can be started because of limited access to vaccines. As current data suggest, vaccination has barely started and progressed in many LMICS, which means that the most vulnerable groups and healthcare workers remain unprotected (figures 1 and 2). In view of the current situation, it is crucial to address if (at all) and why wealthier countries should support less affluent populations.

A Safe and Effective Mucosal RSV Vaccine Consisting of RSV Phosphoprotein and Flagellin Variant

RSV is a major cause of serious acute lower respiratory tract infection in infants and the elderly. No licensed RSV vaccine available thus far calls for the development of vaccines with new target(s) and vaccination strategies. Here, we constructed a recombinant protein, designated P-KFD1, comprised of RSV phosphoprotein (P) and E. coli K12 strain-derived flagellin variant KFD1. Intranasal (i.n.) immunization with P-KFD1 inhibits RSV replication in both upper and lower respiratory tract, and protects mice against lung disease without vaccine-enhanced disease (VED). The P-specific CD4+ T cells provoked by P-KFD1 i.n. immunization, either reside in or migrate to respiratory tract, mediate protection against RSV infection. Sc-RNA seq and CFSE-labeled cell transfer further characterized the Th1 and Th17 responses induced by P-KFD1. Finally, we found the anti-viral protection depends on either IFN-γ or IL-17A. Collectively, P-KFD1 is promising as a safe and effective mucosal vaccine candidate to prevent RSV infection.

Vaccines and drugs under clinical trials for prevention and treatment of COVID-19.

The uncertainty related to prevention and treatment of Coronavirus disease 2019 due to lack of effective vaccine candidates or drug molecules has resulted in extensive spread of infection and mortality worldwide. Although the asymptomatic or mild patients are becoming healthy with regular over-the-counter medicines and proper rest and care, for the severe patients, in the absence of definite cure, different drug combinations are being used to treat on trial basis without the assurance of efficacy and safety. This scenario has however changed now with some medicines including antiviral Remdesivir and Favipiravir and anti-inflammatory drugs like dexamethasone and tocilizumab which have shown some positive results in trials such as decreasing need of mechanical or non-invasive ventilation or mortality. Further, a number of vaccine candidates are currently in pipeline and in advance stages of clinical trials, which will enhance their prospects in determining how the disease will be controlled in the times to come. In this article, an account of the under-trial potential drugs and vaccine candidates has been provided, and their future prospects have been discussed.

A Novel Effective and Safe Vaccine for Prevention of Marek's Disease Caused by Infection with a Very Virulent Plus (vv+) Marek's Disease Virus.

Marek’s disease virus (MDV) is a highly contagious alphaherpesvirus that causes rapid onset lymphoma in chickens. Marek’s disease (MD) is effectively controlled using vaccination; however, MDV continues to break through vaccinal immunity, due to the emergence of highly virulent field strains. Earlier studies revealed that deletion of the meq gene from MDV resulted in an attenuated virus that protects against MD in chickens challenged with highly virulent field strains. However, the meq deleted virus retains the ability to induce significant lymphoid organ atrophy. In a different study, we found that the deletion of the vIL8 gene resulted in the loss of lymphoid organ atrophy in inoculated chickens. Here, we describe the generation of a recombinant MDV from which both meq and vIL8 genes were deleted. In vitro studies revealed that the meq and vIL8 double deletion virus replicated at levels similar to the parental very virulent plus (vv+) virus. In addition, in vivo studies showed that the double deletion mutant virus (686BAC-ΔMeqΔvIL8) conferred protection comparable to CVI988, a commercial vaccine strain, when challenged with a vv+ MDV virus, and significantly reduced lymphoid organ atrophy, when compared to meq null virus, in chickens. In conclusion, our study describes the development of a safe and effective vaccine candidate for prevention of MD in chickens.

Reverse vaccinology approach towards the in-silico multiepitope vaccine development against SARS-CoV-2

Background: The novel severe acute respiratory syndrome related corona virus-2 (SARS-CoV-2) belongs to the “Coronaviridae” family and order “Nidovirales”, which has caused the pandemic coronavirus disease 2019 (COVID-19). SARS-CoV-2 has been spread in more than a 100 countries, and more than a million have lost their lives. Vaccination and immunization could be an effective strategy to combat fatal COVID-19. Methods: For identification of effective vaccine candidate against COVID-19, various immunoinformatics online tools and softwares were used to predict epitopes. Cytotoxic T cell epitopes, helper T cell epitopes, and B cell epitopes from three structural polyproteins (Spike, Membrane, and Nucleocapsid (SMN) based on the binding affinity towards MHC, antigenicity, non-allergenicity, and non-toxicity) were identified for vaccine development. The multiepitope based vaccine was constructed linking two additional adjuvants human beta-defensin-3 and human beta-defensin-2 at N and C terminal, respectively. Results: The constructed vaccine sequence was found to be a good antigen and non-allergen for the human body. The constructed vaccine was docked with the TLR-3 receptor. The docked complex was further taken for molecular dynamics simulations and RMSD was calculated, which showed stable binding of the complex. The codon adaptation index (CAI) of 0.92 and GC content of 55.5% for E. coli (K12 strain) suggested efficient expression of the predicted vaccine. Conclusion: The current study can be helpful in the reduction of time and cost for further experimental validations and could give a valuable contribution against this pandemic.

A single-dose live attenuated chimeric vaccine candidate against Zika virus

The mosquito-borne Zika virus is an emerging pathogen from the Flavivirus genus for which there are no approved antivirals or vaccines. Using the clinically validated PDK-53 dengue virus vaccine strain as a backbone, we created a chimeric dengue/Zika virus, VacDZ, as a live attenuated vaccine candidate against Zika virus. VacDZ demonstrates key markers of attenuation: small plaque phenotype, temperature sensitivity, attenuation of neurovirulence in suckling mice, and attenuation of pathogenicity in interferon deficient adult AG129 mice. VacDZ may be administered as a traditional live virus vaccine, or as a DNA-launched vaccine that produces live VacDZ in vivo after delivery. Both vaccine formulations induce a protective immune response against Zika virus in AG129 mice, which includes neutralising antibodies and a strong Th1 response. This study demonstrates that VacDZ is a safe and effective vaccine candidate against Zika virus.

Immunogenicity and Protective Activity of Pigeon Circovirus Recombinant Capsid Protein Virus-Like Particles (PiCV rCap-VLPs) in Pigeons (Columba livia) Experimentally Infected with PiCV.

Pigeon circovirus (PiCV) is the most recurrent virus diagnosed in pigeons and is among the major causative agents of young pigeon disease syndrome (YPDS). Due to the lack of an established laboratory protocol for PiCV cultivation, development of prophylaxis is hampered. Alternatively, virus-like particles (VLPs), which closely resemble native viruses but lack the viral genetic material, can be generated using a wide range of expression systems and are shown to have strong immunogenicity. Therefore, the use of VLPs provides a promising prospect for vaccine development. In this study, transfected human embryonic kidney (HEK-293) cells, a mammalian expression system, were used to express the PiCV capsid protein (Cap), which is a major component of PiCV and believed to contain antibody epitopes, to obtain self-assembled VLPs. The VLPs were observed to have a spherical morphology with diameters ranging from 12 to 26 nm. Subcutaneous immunization of pigeons with 100 µg PiCV rCap-VLPs supplemented with water-in-oil-in-water (W/O/W) adjuvant induced specific antibodies against PiCV. Observations of the cytokine expression and T-cell proliferation levels in spleen samples showed significantly higher T-cell proliferation and IFN- γ expression in pigeons immunized with VLPs compared to the controls (p < 0.05). Experimentally infected pigeons that were vaccinated with VLPs also showed no detectable viral titer. The results of the current study demonstrated the potential use of PiCV rCap-VLPs as an effective vaccine candidate against PiCV.

Characterisation of a New Molecule Based on Two E2 Sequences from Bovine Viral Diarrhoea-mucosal Disease Virus Fused To the Human Immunoglobulin Fc Fragment.

IntroductionProper conformational arrangement of the E2 molecules of bovine viral diarrhoea-mucosal disease virus (BVD-MDV) is crucial to obtain an effective recombinant vaccine candidate against the disease. In this study, we characterised a new molecule composed of two distinct sequences of the E2 glycoprotein of BVD-MDV and the Fc fragment of human immunoglobulin (BVDE2Fc).Materials and MethodsThe chimaeric protein was expressed in mammalian cell lines of different species by adenoviral transduction and purified by immobilised metal-affinity chromatography. The N-glycans were profiled by HPLC, and the BVDE2Fc immunogenicity was assessed in male mice. The antigen-antibody reactions were evaluated by ELISA.ResultsThe MDBK cell line was selected from among five for the final production of BVDE2Fc. After purification to over 90%, the N-glycan profile showed neutral and complex oligosaccharides. The mouse immunisation induced a strong humoral response, which produced antibodies able to attach to conformational epitopes on E2 molecules, while the Fc fragment barely contributed to the immune response. Additionally, BVDE2Fc attached to antibodies from bovine sera positive to distinct BVD-MDV subtypes, whereas the loss of BVDE2Fc structure during the deglycosylation process considerably diminished those interactions.ConclusionThese results demonstrate that the structure of E2 molecules arranged in tandem and attached to an Fc fragment could represent a viable design for future vaccine candidates against BVD-MD.

Reverse vaccinology approach towards the in-silico multiepitope vaccine development against SARS-CoV-2.

Background: The novel severe acute respiratory syndrome related corona virus-2 (SARS-CoV-2) belongs to the "Coronaviridae" family and order "Nidovirales", which has caused the pandemic coronavirus disease 2019 (COVID-19). SARS-CoV-2 has been spread in more than a 100 countries, and more than a million have lost their lives. Vaccination and immunization could be an effective strategy to combat fatal COVID-19. Methods: For identification of effective vaccine candidate against COVID-19, various immunoinformatics online tools and softwares were used to predict epitopes. Cytotoxic T cell epitopes, helper T cell epitopes, and B cell epitopes from three structural polyproteins (Spike, Membrane, and Nucleocapsid (SMN) based on the binding affinity towards MHC, antigenicity, non-allergenicity, and non-toxicity) were identified for vaccine development. The multiepitope based vaccine was constructed linking two additional adjuvants human beta-defensin-3 and human beta-defensin-2 at N and C terminal, respectively. Results: The constructed vaccine sequence was found to be a good antigen and non-allergen for the human body. The constructed vaccine was docked with the TLR-3 receptor. The docked complex was further taken for molecular dynamics simulations and RMSD was calculated, which showed stable binding of the complex. The codon adaptation index (CAI) of 0.92 and GC content of 55.5% for E. coli (K12 strain) suggested efficient expression of the predicted vaccine. Conclusion: The current study can be helpful in the reduction of time and cost for further experimental validations and could give a valuable contribution against this pandemic.

Immunogenic characterization and protective efficacy of recombinant CsgA, major subunit of curli fibers, against Vibrio parahaemolyticus.

Vibrio parahaemolyticus is one of the major pathogens responsible for vibriosis and zoonotic infections in teleosts, marine invertebrates, and also humans through consumption of contaminated or unprocessed seafood. Emergence of resistance against current accessible antibiotics and spread to the food chain and environment necessitate the development of safe and effective subunit vaccine against this bacterium. Many bacteria including V. parahaemolyticus produce extracellular curli fibrils, heteropolymeric filaments of major and minor subunit, which have been implicated in adhesion, biofilm formation, and virulence. Adhesins are the primary contact points with the host which help in establishing infection and colonization. CsgA, an adhesin, is the major structural component of the curli fiber that forms homopolymers of several hundred units. Due to their exposure on the cell surface, the curli fibers are recognized by the host's immune system, would generate high immune response, and therefore can serve as effective vaccine candidate. In the present study, we describe characterization of the csgA gene, and preparation of recombinant soluble CsgA of V. parahaemolyticus (rVpCsgA), and evaluation of its vaccine potential. Immunization of BALB/c mice with the rVpCsgA mounted a strong immune response. Cellular immune assays such as antibody isotyping, in vitro splenocyte proliferation analysis, and cytokine profiling revealed mixed T-helper cell immune response. The anti-rVpCsgA antiserum was agglutination positive and specifically cross-reacted with the curli CsgA present on the outer membrane of V. parahaemolyticus cells, thus demonstrating its neutralization potential. One hundred percent survival of the immunized mice upon challenge with the lethal dosage of the bacterium established that the rVpCsgA could serve as an effective vaccine against the bacterium. KEY POINTS: • Recombinant histidine-tagged CsgA of V. parahaemolyticus, rVpCsgA, was purified. • The rVpCsgA immunization produced mixed immune response and agglutinating antibodies. • Immunization with the rVpCsgA protected mice against V. parahaemolyticus challenge.

High Efficacy of a Low Dose Candidate Malaria Vaccine, R21 in 1 Adjuvant Matrix-M™, with Seasonal Administration to Children in Burkina Faso

Background: Stalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 55·8% (97·5% confidence interval [CI], 51-60) efficacy over 12 months in African children. Methods: We conducted a double-blind, randomised, controlled trial of a low-dose circumsporozoite protein-based vaccine, R21, with two different doses of adjuvant, Matrix-M™ (MM), in children aged 5-17 months in Nanoro, Burkina Faso, a highly seasonal malaria transmission setting. Three vaccinations were administered at 4-week intervals prior to the malaria season with a fourth dose one year later. Vaccine safety, immunogenicity and efficacy were evaluated over one year. Findings: 450 children were randomised to receive the R21/MM vaccine or a control rabies vaccine. R21/MM had a 43 favourable safety profile and was well-tolerated. At 6 months, 43/146 (29·5%) who received R21/MM with low44 dose adjuvant, 38/146 (26%) who received R21/MM with high-dose adjuvant, and 105/147 (71·4%) who received the rabies vaccine developed clinical malaria. Vaccine efficacy (VE) was 74% (95% CI, 63-82) and 77% (95% CI, 67-84) in the low- and high-dose adjuvant groups, respectively. At 1 year, VE remained high at 77% (95% CI, 67-84) in the high-dose adjuvant group. Participants vaccinated with R21/MM showed high titres of malaria-specific anti-NANP antibodies 28 days after the third vaccination, which were almost doubled with the higher adjuvant dose. Titres waned but were boosted to levels similar to peak titres following the primary series of vaccinations after a fourth dose administered one year later. Interpretation: R21/Matrix-M appears safe and very immunogenic in African children, and demonstrates promising high-level efficacy. Trial Registration: ClinicalTrials.gov number: NCT03896724. Funding: The European & Developing Countries Clinical Trials Partnership (EDCTP), The Wellcome Trust and the NIHR Oxford Biomedical Research Centre. Declaration of Interest: AVSH and KJE are named as co-inventors on patent applications related to R21. GG, LF, JR and PP-A are employees of Novavax, developers of the Matrix-M adjuvant, and US is an employee of the Serum Institute of India Private Ltd, co-developer of the R21/MM vaccine. Other authors declare no competing interests. Ethical Approval: The trial was approved by the Comite d’Ethique pour la Recherche en Sante, Burkina Faso (CERS, reference number 2019-01-012), and by the national regulatory authority, Agence National de Regulation Pharmaceutique, Burkina Faso (ANRP, reference number 5005420193E). Ethical approval was also granted in the United Kingdom by the Oxford Tropical Research Ethics Committee (OxTREC reference number 19-19).

Innate Immune Subversion Strategies of Human Flaviviruses.

Flavivirus is a genus of medically important viruses, including Dengue virus (DENV), Zika virus (ZIKV), Yellow Fever virus (YFV), West Nile virus (WNV), Japanese encephalitis virus (JEV), etc. The global burden of these acute infection-causing viruses is ever-increasing. Primary febrile symptoms of most of these viruses can progress to hemorrhagic or neurological complications, and some like JEV, YFV have a greater than 15% mortality. The absence of antiviral therapy and highly effective vaccine candidates for these viruses highlights the need for research into virulence and immune evasion mechanisms at the molecular level. Interaction with the host needs to be carefully dissected to narrow down to a list of necessary factors for virus survival within the host. This review attempts to comprehensively compile research efforts made in the field of innate immune subversion strategies employed by the human Flaviviruses.

Immunogenicity of Subunit Vaccine of E2 Protein Against Atypical Porcine Pestivirus in Pigs

An atypical porcine pestivirus (APPV) causes congenital tremor (CT) type A-II in piglets and has caused considerable financial losses to the pig industry worldwide. This study aimed to develop an effective vaccine candidate against APPV. In this study, we constructed a prokaryotic expressing APPV E2 protein by Escherichia coli and evaluated the immunogenicity of the APPV E2 subunit vaccine with three different adjuvants in piglets by E2-enzyme-linked immunosorbent assay antibody and the protection against APPV challenge in pigs. E2 protein was successfully expressed by the Escherichia coli prokaryotic expression system firstly, and was confirmed by western blot assay. The E2-enzyme-linked immunosorbent assay antibody detection method was established. Vaccined piglets mounted virus-specific IgG responses. The E2 protein emulsified with ISA 201VG and Gel 02 adjuvant induced significantly higher levels of antibodies than those emulsified with IMS 1313VG adjuvant. The vaccine with ISA 201VG adjuvant had highest antibody levels and can protect against APPV infection. The results demonstrated that Escherichia coli-expressed E2 is mounting an immune response in pigs, E2 subunit vaccine maybe a potential vaccine candidate for the prevention of APPV infection, ISA 201VG and Gel 02 adjuvant can be used as candidate adjuvants for vaccines. This study provides a basis for the further research of APPV vaccine.