Norovirus Vaccines: Current Clinical Development and Challenges

Noroviruses are the major viral pathogens causing epidemic and endemic acute gastroenteritis with significant morbidity and mortality. While vaccines against norovirus diseases have been shown to be of high significance, the development of a broadly effective norovirus vaccine remains difficult, owing to the wide genetic and antigenic diversity of noroviruses with multiple co-circulated variants of various genotypes. In addition, the absence of a robust cell culture system, an efficient animal model, and reliable immune markers of norovirus protection for vaccine evaluation further hinders the developmental process. Among the vaccine candidates that are currently under clinical studies, recombinant VP1-based virus-like particles (VLPs) that mimic major antigenic features of noroviruses are the common ones, with proven safety, immunogenicity, and protective efficacy, supporting a high success likelihood of a useful norovirus vaccine. This short article reviews the recent progress in norovirus vaccine development, focusing on those from recent clinical studies, as well as summarizes the barriers that are being encountered in this developmental process and discusses issues of future perspective.

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MVA vector expression of SARS-CoV-2 spike protein and protection of adult Syrian hamsters against SARS-CoV-2 challenge

npj Vaccines ◽

10.1038/s41541-021-00410-8 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Clement A. Meseda ◽

Charles B. Stauft ◽

Prabhuanand Selvaraj ◽

Christopher Z. Lien ◽

Cyntia Pedro ◽

...

Keyword(s):

Vaccine Development ◽

Protective Efficacy ◽

Neutralizing Antibody ◽

Virus Shedding ◽

Vaccine Candidates ◽

Syrian Hamsters ◽

Modified Vaccinia Virus Ankara ◽

Dose Ranging ◽

Subcutaneous Immunization

AbstractNumerous vaccine candidates against SARS-CoV-2, the causative agent of the COVID-19 pandemic, are under development. The majority of vaccine candidates to date are designed to induce immune responses against the viral spike (S) protein, although different forms of S antigen have been incorporated. To evaluate the yield and immunogenicity of different forms of S, we constructed modified vaccinia virus Ankara (MVA) vectors expressing full-length S (MVA-S), the RBD, and soluble S ectodomain and tested their immunogenicity in dose-ranging studies in mice. All three MVA vectors induced spike-specific immunoglobulin G after one subcutaneous immunization and serum titers were boosted following a second immunization. The MVA-S and MVA-ssM elicited the strongest neutralizing antibody responses. In assessing protective efficacy, MVA-S-immunized adult Syrian hamsters were challenged with SARS-CoV-2 (USA/WA1/2020). MVA-S-vaccinated hamsters exhibited less severe manifestations of atypical pneumocyte hyperplasia, hemorrhage, vasculitis, and especially consolidation, compared to control animals. They also displayed significant reductions in gross pathology scores and weight loss, and a moderate reduction in virus shedding was observed post challenge in nasal washes. There was evidence of reduced viral replication by in situ hybridization, although the reduction in viral RNA levels in lungs and nasal turbinates did not reach significance. Taken together, the data indicate that immunization with two doses of an MVA vector expressing SARS-CoV-2 S provides protection against a stringent SARS-CoV-2 challenge of adult Syrian hamsters, reaffirm the utility of this animal model for evaluating candidate SARS-CoV-2 vaccines, and demonstrate the value of an MVA platform in facilitating vaccine development against SARS-CoV-2.

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Protective efficacy of rhesus adenovirus COVID-19 vaccines against mouse-adapted SARS-CoV-2

10.1101/2021.06.14.448461 ◽

2021 ◽

Author(s):

Lisa Tostanoski ◽

Lisa Gralinski ◽

David Martinez ◽

Alexandra Schaefer ◽

Shant Mahrokhian ◽

...

Keyword(s):

Viral Replication ◽

Vaccine Development ◽

Protective Efficacy ◽

Rapid Development ◽

Model Systems ◽

Wild Type ◽

Challenge Virus ◽

Vaccine Candidates ◽

Immune Correlates ◽

Adenovirus Vectors

The global COVID-19 pandemic has sparked intense interest in the rapid development of vaccines as well as animal models to evaluate vaccine candidates and to define immune correlates of protection. We recently reported a mouse-adapted SARS-CoV-2 virus strain (MA10) with the potential to infect wild-type laboratory mice, driving high levels of viral replication in respiratory tract tissues as well as severe clinical and respiratory symptoms, aspects of COVID-19 disease in humans that are important to capture in model systems. We evaluated the immunogenicity and protective efficacy of novel rhesus adenovirus serotype 52 (RhAd52) vaccines against MA10 challenge in mice. Baseline seroprevalence is lower for rhesus adenovirus vectors than for human or chimpanzee adenovirus vectors, making these vectors attractive candidates for vaccine development. We observed that RhAd52 vaccines elicited robust binding and neutralizing antibody titers, which inversely correlated with viral replication after challenge. These data support the development of RhAd52 vaccines and the use of the MA10 challenge virus to screen novel vaccine candidates and to study the immunologic mechanisms that underscore protection from SARS-CoV-2 challenge in wild-type mice.

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A multi-method and structure-based in silico vaccine designing against Helicobacter pylori employing immuno-informatics approach

Current Proteomics ◽

10.2174/1570164617999200414120231 ◽

2020 ◽

Vol 17 ◽

Author(s):

Anam Naz ◽

Tahreem Zaheer ◽

Hamza Arshad Dar ◽

Faryal Mehwish Awan ◽

Ayesha Obaid ◽

...

Keyword(s):

Helicobacter Pylori ◽

Vaccine Development ◽

Amino Acid Sequences ◽

The Body ◽

New Drugs ◽

Toll Like Receptor ◽

Peptide Vaccines ◽

Hla Alleles ◽

Vaccine Candidates ◽

H Pylori

Background: Helicobacter pylori infection and its treatment still remains a challenge to human health worldwide. A variety of antibiotics and combination therapies are currently used to treat H. pylori induced ulcers and carcinoma; however, no effective treatment is available to eliminate the pathogen from the body. Additionally, antibiotic resistance is also one of the main reasons for prolonged and persistent infection. Aim of the study: Until new drugs are available for this infection, vaccinology seems the only alternative opportunity to exploit against H. pylori induced diseases. Methods: Multiple epitopes prioritized in our previous study have been tested for their possible antigenic combinations, and results in 169-mer and 183-mer peptide vaccines containing the amino acid sequences of 3 and 4 epitopes respectively, along with adjuvant (Cholera Toxin Subunit B adjuvant at 5’ end) and linkers (GPGPG and EAAAK). Results: Poly-epitope proteins proposed as potential vaccine candidates against H. pylori include SabAHP0289-Omp16-VacA (SHOV), VacA-Omp16-HP0289-FecA (VOHF), VacA-Omp16-HP0289-SabA (VOHS), VacA-Omp16-HP0289-BabA (VOHB), VacA-Omp16-HP0289-SabA-FecA (VOHSF), VacAOmp16-HP0289-SabA-BabA (VOHSB) and VacA-Omp16-HP0289-BabA-SabA (VOHBS). Structures of these poly-epitope peptide vaccines have been modelled and checked for their affinity with HLA alleles and receptors. These proposed poly-epitope vaccine candidates bind efficiently with A2, A3, B7 and DR1 superfamilies of HLA alleles. They can also form stable and significant interactions with Toll-like receptor 2 and Toll-like receptor 4. Conclusion: Results suggest that these multi-epitopic vaccines can elicit a significant immune response against H. pylori and can be tested further for efficient vaccine development.

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SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates

npj Vaccines ◽

10.1038/s41541-021-00292-w ◽

2021 ◽

Vol 6 (1) ◽

Cited By ~ 3

Author(s):

Nikolaos C. Kyriakidis ◽

Andrés López-Cortés ◽

Eduardo Vásconez González ◽

Alejandra Barreto Grimaldos ◽

Esteban Ortiz Prado

Keyword(s):

Neutralizing Antibodies ◽

Large Scale ◽

Vaccine Development ◽

Rna Virus ◽

Protein S ◽

Effective Vaccine ◽

Phase 3 ◽

Vaccine Candidates ◽

Advantages And Disadvantages ◽

The World

AbstractThe new SARS-CoV-2 virus is an RNA virus that belongs to the Coronaviridae family and causes COVID-19 disease. The newly sequenced virus appears to originate in China and rapidly spread throughout the world, becoming a pandemic that, until January 5th, 2021, has caused more than 1,866,000 deaths. Hence, laboratories worldwide are developing an effective vaccine against this disease, which will be essential to reduce morbidity and mortality. Currently, there more than 64 vaccine candidates, most of them aiming to induce neutralizing antibodies against the spike protein (S). These antibodies will prevent uptake through the human ACE-2 receptor, thereby limiting viral entrance. Different vaccine platforms are being used for vaccine development, each one presenting several advantages and disadvantages. Thus far, thirteen vaccine candidates are being tested in Phase 3 clinical trials; therefore, it is closer to receiving approval or authorization for large-scale immunizations.

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In silico characterisation of putative Plasmodium falciparum vaccine candidates in African malaria populations

Scientific Reports ◽

10.1038/s41598-021-95442-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

O. Ajibola ◽

M. F. Diop ◽

A. Ghansah ◽

L. Amenga-Etego ◽

L. Golassa ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Malaria Vaccine ◽

Transmembrane Domain ◽

Vaccine Development ◽

Balancing Selection ◽

Immune Recognition ◽

African Countries ◽

Vaccine Candidates ◽

D Values ◽

Tajima’S D

AbstractGenetic diversity of surface exposed and stage specific Plasmodium falciparum immunogenic proteins pose a major roadblock to developing an effective malaria vaccine with broad and long-lasting immunity. We conducted a prospective genetic analysis of candidate antigens (msp1, ama1, rh5, eba175, glurp, celtos, csp, lsa3, Pfsea, trap, conserved chrom3, hyp9, hyp10, phistb, surfin8.2, and surfin14.1) for malaria vaccine development on 2375 P. falciparum sequences from 16 African countries. We described signatures of balancing selection inferred from positive values of Tajima’s D for all antigens across all populations except for glurp. This could be as a result of immune selection on these antigens as positive Tajima’s D values mapped to regions with putative immune epitopes. A less diverse phistb antigen was characterised with a transmembrane domain, glycophosphatidyl anchors between the N and C- terminals, and surface epitopes that could be targets of immune recognition. This study demonstrates the value of population genetic and immunoinformatic analysis for identifying and characterising new putative vaccine candidates towards improving strain transcending immunity, and vaccine efficacy across all endemic populations.

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Design of the Recombinant Influenza Neuraminidase Antigen is Crucial for its Biochemical Properties and Protective Efficacy

Journal of Virology ◽

10.1128/jvi.01160-21 ◽

2021 ◽

Author(s):

Jin Gao ◽

Laura Klenow ◽

Lisa Parsons ◽

Tahir Malik ◽

Je-Nie Phue ◽

...

Keyword(s):

Single Dose ◽

Vaccine Development ◽

Protective Efficacy ◽

Biochemical Properties ◽

Cell System ◽

Influenza Vaccines ◽

H1n1 Vaccine ◽

Protective Properties ◽

Head Domain ◽

Tetramerization Domain

Supplementing influenza vaccines with recombinant neuraminidase (rNA) antigens remains a promising approach for improving the suboptimal vaccine efficacy. However, correlations among rNA designs, properties, and protection have not been systematically investigated. Here, we performed a comparative analysis of several rNAs produced using the baculovirus/insect cell system. The rNAs were designed with different tetramerization motifs and NA domains from a recent H1N1 vaccine strain (A/Brisbane/02/2018) and were compared for enzymatic property, antigenicity, stability, and protection in mice. We found that distinct enzymatic properties are associated with rNAs containing the NA head-domain versus the full-ectodomain, formation of higher order rNA oligomers is tetramerization domain-dependent, whereas protective efficacy is more contingent on the combination of the tetramerization and NA domains. Following single-dose immunizations, a rNA possessing the full-ectodomain and the tetramerization motif from the human vasodilator-stimulated phosphoprotein provided much better protection than a rNA with ∼10-fold more enzymatically active molecules that is comprised of the head-domain and the same tetramerization motif. In contrast, these two rNA designs provided comparable protection when the tetramerization motif from the tetrabrachion protein was used instead. These findings demonstrate that individual rNAs should be thoroughly evaluated for vaccine development, as the heterologous domain combination can result in rNAs with similar key attributes but vastly differ in protection. IMPORTANCE For several decades it has been proposed that influenza vaccines could be supplemented with recombinant neuraminidase (rNA) to improve the efficacy. However, some key questions for manufacturing stable and immunogenic rNA remain to be answered. We show here that the tetramerization motifs and NA domains included in the rNA construct design can have a profound impact on the biochemical, immunogenic and protective properties. We also show that the single-dose immunization regimen is more informative for assessing the rNA immune response and protective efficacy, which is surprisingly more dependent on the specific combination of NA and tetramerization domains than common attributes for evaluating NA. Our findings may help to optimize the design of rNAs that can be used to improve or develop influenza vaccines.

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Broad neutralization of H1 and H3 viruses by adjuvanted influenza HA stem vaccines in nonhuman primates

Science Translational Medicine ◽

10.1126/scitranslmed.abe5449 ◽

2021 ◽

Vol 13 (583) ◽

pp. eabe5449

Author(s):

Nicole Darricarrère ◽

Yu Qiu ◽

Masaru Kanekiyo ◽

Adrian Creanga ◽

Rebecca A. Gillespie ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Nonhuman Primates ◽

Vaccine Development ◽

Protective Efficacy ◽

Neutralizing Antibody ◽

Gene Families ◽

Influenza Viruses ◽

Public Health Importance ◽

Water Emulsion

Seasonal influenza vaccines confer protection against specific viral strains but have restricted breadth that limits their protective efficacy. The H1 and H3 subtypes of influenza A virus cause most of the seasonal epidemics observed in humans and are the major drivers of influenza A virus–associated mortality. The consequences of pandemic spread of COVID-19 underscore the public health importance of prospective vaccine development. Here, we show that headless hemagglutinin (HA) stabilized-stem immunogens presented on ferritin nanoparticles elicit broadly neutralizing antibody (bnAb) responses to diverse H1 and H3 viruses in nonhuman primates (NHPs) when delivered with a squalene-based oil-in-water emulsion adjuvant, AF03. The neutralization potency and breadth of antibodies isolated from NHPs were comparable to human bnAbs and extended to mismatched heterosubtypic influenza viruses. Although NHPs lack the immunoglobulin germline VH1-69 residues associated with the most prevalent human stem-directed bnAbs, other gene families compensated to generate bnAbs. Isolation and structural analyses of vaccine-induced bnAbs revealed extensive interaction with the fusion peptide on the HA stem, which is essential for viral entry. Antibodies elicited by these headless HA stabilized-stem vaccines neutralized diverse H1 and H3 influenza viruses and shared a mode of recognition analogous to human bnAbs, suggesting that these vaccines have the potential to confer broadly protective immunity against diverse viruses responsible for seasonal and pandemic influenza infections in humans.

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Protective Vaccine Efficacy of the Complete Form of PPE39 Protein from Mycobacterium tuberculosis Beijing/K Strain in Mice

Clinical and Vaccine Immunology ◽

10.1128/cvi.00219-17 ◽

2017 ◽

Vol 24 (11) ◽

Cited By ~ 4

Author(s):

Ahreum Kim ◽

Yun-Gyoung Hur ◽

Sunwha Gu ◽

Sang-Nae Cho

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

T Cell ◽

Vaccine Development ◽

Protective Efficacy ◽

Interleukin 2 ◽

T Cell Epitopes ◽

Content Type ◽

Complete Form ◽

Ifn Γ

ABSTRACT The aim of this study was to evaluate the protective efficacy of MTBK_24820, a complete form of PPE39 protein derived from a predominant Beijing/K strain of Mycobacterium tuberculosis in South Korea. Mice were immunized with MTKB_24820, M. bovis Bacilli Calmette-Guérin (BCG), or adjuvant prior to a high-dosed Beijing/K strain aerosol infection. After 4 and 9 weeks, bacterial loads were determined and histopathologic and immunologic features in the lungs and spleens of the M. tuberculosis-infected mice were analyzed. Putative immunogenic T-cell epitopes were examined using synthetic overlapping peptides. Successful immunization of MTBK_24820 in mice was confirmed by increased IgG responses (P < 0.05) and recalled gamma interferon (IFN-γ), interleukin-2 (IL-2), IL-6, and IL-17 responses (P < 0.05 or P < 0.01) to MTBK_24820. After challenge with the Beijing/K strain, an approximately 0.5 to 1.0 log10 reduction in CFU in lungs and fewer lung inflammation lesions were observed in MTBK_24820-immunized mice compared to those for control mice. Moreover, MTBK_24820 immunization elicited significantly higher numbers of CD4+ T cells producing protective cytokines, such as IFN-γ and IL-17, in lungs and spleens (P < 0.01) and CD4+ multifunctional T cells producing IFN-γ, tumor necrosis factor alpha (TNF-α), and/or IL-17 (P < 0.01) than in control mice, suggesting protection comparable to that of BCG against the hypervirulent Beijing/K strain. The dominant immunogenic T-cell epitopes that induced IFN-γ production were at the N terminus (amino acids 85 to 102 and 217 to 234). Its vaccine potential, along with protective immune responses in vivo, may be informative for vaccine development, particularly in regions where the M. tuberculosis Beijing/K-strain is frequently isolated from TB patients.

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Progress and challenges in TB vaccine development

F1000Research ◽

10.12688/f1000research.13588.1 ◽

2018 ◽

Vol 7 ◽

pp. 199 ◽

Cited By ~ 51

Author(s):

Gerald Voss ◽

Danilo Casimiro ◽

Olivier Neyrolles ◽

Ann Williams ◽

Stefan H.E. Kaufmann ◽

...

Keyword(s):

Clinical Trials ◽

Vaccine Development ◽

Scientific Progress ◽

Human Infection ◽

Experimental Medicine ◽

Vaccine Platform ◽

Vaccine Candidates ◽

Clinical Endpoints ◽

Immune Correlates ◽

Efficacy Trials

The Bacille Calmette Guerin (BCG) vaccine can provide decades of protection against tuberculosis (TB) disease, and although imperfect, BCG is proof that vaccine mediated protection against TB is a possibility. A new TB vaccine is, therefore, an inevitability; the question is how long will it take us to get there? We have made substantial progress in the development of vaccine platforms, in the identification of antigens and of immune correlates of risk of TB disease. We have also standardized animal models to enable head-to-head comparison and selection of candidate TB vaccines for further development. To extend our understanding of the safety and immunogenicity of TB vaccines we have performed experimental medicine studies to explore route of administration and have begun to develop controlled human infection models. Driven by a desire to reduce the length and cost of human efficacy trials we have applied novel approaches to later stage clinical development, exploring alternative clinical endpoints to prevention of disease outcomes. Here, global leaders in TB vaccine development discuss the progress made and the challenges that remain. What emerges is that, despite scientific progress, few vaccine candidates have entered clinical trials in the last 5 years and few vaccines in clinical trials have progressed to efficacy trials. Crucially, we have undervalued the knowledge gained from our “failed” trials and fostered a culture of risk aversion that has limited new funding for clinical TB vaccine development. The unintended consequence of this abundance of caution is lack of diversity of new TB vaccine candidates and stagnation of the clinical pipeline. We have a variety of new vaccine platform technologies, mycobacterial antigens and animal and human models. However, we will not encourage progression of vaccine candidates into clinical trials unless we evaluate and embrace risk in pursuit of vaccine development.

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Assessment of immunogenicity and protective efficacy of ZyCoV-D DNA vaccine candidates in Rhesus macaques against SARS-CoV-2 infection

10.1101/2021.02.02.429480 ◽

2021 ◽

Author(s):

Pragya D Yadav ◽

Sanjay Kumar ◽

Kshitij Agarwal ◽

Mukul Jain ◽

Dilip R Patil ◽

...

Keyword(s):

Vaccine Candidate ◽

Protective Efficacy ◽

Rhesus Macaques ◽

Herd Immunity ◽

Lavage Fluid ◽

Injection System ◽

Protective Measure ◽

Vaccine Candidates ◽

Virus Challenge ◽

Syringe Needle

AbstractVaccines remain the key protective measure to achieve herd immunity to control the disease burden and stop COVID-19 pandemic. We have developed and assessed the immunogenicity and protective efficacy of two formulations (1mg and 2mg) of ZyCoV-D (a plasmid DNA based vaccine candidates) administered through Needle Free Injection System (NFIS) and syringe-needle (intradermal) in rhesus macaques with three dose vaccine regimens. The vaccine candidate 2mg dose administered using Needle Free Injection System (NFIS) elicited a significant immune response with development of SARS-CoV-2 S1 spike region specific IgG and neutralizing antibody (NAb) titers during the immunization phase and significant enhancement in the levels after the virus challenge. In 2 mg NFIS group the IgG and NAb titers were maintained and showed gradual rise during the immunization period (15 weeks) and till 2 weeks after the virus challenge. It also conferred better protection to macaques evident by the viral clearance from nasal swab, throat swab and bronchoalveolar lavage fluid specimens in comparison with macaques from other immunized groups. In contrast, the animals from placebo group developed high levels of viremia and lung disease following the virus challenge. Besides this, the vaccine candidate also induced increase lymphocyte proliferation and cytokines response (IL-6, IL-5).The administration of the vaccine candidate with NFIS generated a better immunogenicity response in comparison to syringe-needle (intradermal route). The study demonstrated immunogenicity and protective efficacy of the vaccine candidate, ZyCoV-D in rhesus macaques.

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