Development of Vaccines Against Emerging Pathogens

Editors

Katie Ewer

University of Oxford

Teresa Lambe

University of Oxford

Neeltje van Doremalen

Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases (NIH)

Impact

Review

18 March 2021

The Integration of Human and Veterinary Studies for Better Understanding and Management of Crimean-Congo Haemorrhagic Fever

Ciaran Gilbride

, 6 more and

Sandra Belij-Rammerstorfer

7,231 views

12 citations

Durability of the immune response following DNA prime rAd5-GP boost. Cynomolgus macaques were primed with plasmid vectors encoding GP(Z) and GP(S/G) one or three times. Eight weeks after the last DNA immunization 4 NHP's from each group were boosted with 1011 PFU of rAd5-GP vaccine. Blood sampling for anti-GP antibody and T-cell analysis were collected 130–160 weeks after the rAd5-GP boost, and at 159 weeks from four animals which received only a single DNA prime immunization without a boost. PBMCs were stimulated with EBOV GP peptides. The magnitude of antigen-specific cytokine response and pattern of CD4+ (A,B) and CD8+ (C,D) T-cells (G:IFNγ, T:TNFa, and 2:IL-2). (E) Specific anti-GP antibody titers were measured using ELISA. (F) Ebola GP specific CD4+ and CD8+ T-cells after rAd5 GP boost that was given 159 weeks after a single DNA prime. Statistical analysis between two groups was performed using an unpaired student's t-test, comparison between more than two groups were performed using a one-way ANOVA with Tukey's post hoc test; *p < 0.05, **p < 0.01, ***p < 0.001,****p < 0.0001; mean ± standard deviation shown.

Original Research

09 March 2021

Ebola-GP DNA Prime rAd5-GP Boost: Influence of Prime Frequency and Prime/Boost Time Interval on the Immune Response in Non-human Primates

Hadar Marcus

, 9 more and

Nancy J. Sullivan

2,756 views

4 citations

(A) Overall predictive performance of Predivac-3.0 measured by leave-one-out cross-validation over 46 HLA class I alleles having more than 25 associated peptide ligands in PredivacDB. The benchmark against pan-specific methods (NetMHCpan 4.0, Pickpocket, PSSMHCpan and SMM-align) using (B) a dataset of experimentally validated CD8+ T-cell epitopes derived from the IEDB Analysis Resource (IEDB-dataset) and (C) a dataset of high-affinity peptide ligands derived from the Dana-Farber Repository for Machine Learning in Immunology (DFRMLI-dataset) (See Material and Methods).

Original Research

26 February 2021

A Proteome-Wide Immunoinformatics Tool to Accelerate T-Cell Epitope Discovery and Vaccine Design in the Context of Emerging Infectious Diseases: An Ethnicity-Oriented Approach

Patricio Oyarzun

, 7 more and

Bostjan Kobe

10,021 views

23 citations

Studies of humoral and cellular responses in Evola virus disease (EVD) survivors and in vaccinated individuals is one strategy to establish correlates of protection. However, controlled challenge studies cannot be performed in humans. The second strategy to identify correlates of protection is the analysis of immune responses in challenge animal models, which allows to compare immunity in protected and not protected animals. Figure created with BioRender.

Review

19 February 2021

Ebolavirus: Comparison of Survivor Immunology and Animal Models in the Search for a Correlate of Protection

Stephanie Longet

, 2 more and

Tom Tipton

8,912 views

18 citations

Left panel: A schematic overview of conventional influenza virus vaccine platforms, including the live attenuated vaccine (LAIV), the split virion inactivated influenza vaccine (IIV) or IIV sub-virion vaccine, which has HA>NA content. Right panel: Newer vaccines being developed include recombinant HA protein, virus-like-particles or nucleic acid-based vaccines such as DNA or mRNA platforms. Center panel: Schematic overview of how non-replicating adenoviral (Ad) vectored vaccines work. DNA sequence encoding an influenza virus antigen is inserted into the dsDNA genome of the Ad vector under the control of a powerful promoter to drive expression. Once immunized, the DNA sequence coding for the influenza antigen is transcribed into mRNA and translated into protein which is expressed inside the host cells at the site of injection and/or within draining lymph nodes. This results in a robust CD8+ T cell response, as well as humoral immune responses directed towards the encoded transgene antigen. Note: the trimeric stalk of HA, or tetrameric stalk of NA are not shown in the diagram and icons are not to scale. Figure created with ©BioRender - Biorender.com.

Review

29 January 2021

Adenoviral Vectors as Vaccines for Emerging Avian Influenza Viruses

Lucas J. Kerstetter

, 2 more and

Lynda Coughlan

19,979 views

29 citations

Five days after the vaccination of C57Bl6 mice, splenocytes and lung cells were isolated from vaccinated and control mice (PBS) and in vitro restimulated with S1 and S2 overlapping peptides from SARS-CoV-2 protein in the presence of protein transport inhibitor, brefeldin A for the last 5 h of culture. After 20 h of culture, ICS was performed to quantify protein S-specific CD8+ and CD4+ T-cell responses. Cytokine expression in the presence of no peptides was considered background and it was subtracted from the responses measured from peptide pool stimulated samples for each individual mouse. (A, B) CD8+ T cells from spleen and lungs expressing IFNγ, TNFα, and IL-2 in response to S1 and S2 peptide pool; (C, D) CD4+ T cells from spleen and lungs expressing IFNγ, TNFα, and IL-2 in response to S1 and S2 peptide pool; (E) Representative dot plot of gated CD8+ T cells in lungs expressing indicated cytokines (IFNγ; IL-2, and TNFα) in vaccinated and non-vaccinated (PBS, control) HLA-A2 mice at day 5 (F) Proportion of antigen (protein S)-experienced CD8+ and CD4+ T cells isolated from spleen and lung tissue expressing IFNγ, TNFα, or IL-2 after o/n stimulation with S1 + S2 peptides. Pie charts corresponding to cytokine profiles of CD8+ and CD4+ T cells isolated from spleen and lung tissue; (G) Pie charts corresponding to cytokine profiles of CD8+ CD4+ T cells isolated from spleen and lung tissue after o/n stimulation with S1 + S2 peptides. Assessment of the mean proportion of cells making any combination of one to three cytokines (IFN-γ, TNFα, IL-2). Data represent at least two technical replicates with three to six independent biologic replicates per group. *p<0.05, ***p<0.001. Kruskal-Wallis ANOVA with Dunn’s multiple comparisons tests were applied. Asterisks (*) above or inside the column denote significant differences between indicated T cells producing cytokines in vaccine versus control (PBS) at 0.05 alpha level. ANOVA, analysis of variance; ICS, intracellular cytokine staining; IFN, interferon; IL, interleukin; PBS, phosphate-buffered saline; TNF, tumor necrosis factor.

Original Research

26 January 2021

Induction of SARS-CoV-2 Protein S-Specific CD8+ T Cells in the Lungs of gp96-Ig-S Vaccinated Mice

Eva Fisher

, 6 more and

Natasa Strbo

10,826 views

13 citations

Mini Review

06 November 2020

Adjuvants for Coronavirus Vaccines

Zhihui Liang

, 10 more and

Bingbing Sun

Vaccine development utilizing various platforms is one of the strategies that has been proposed to address the coronavirus disease 2019 (COVID-19) pandemic. Adjuvants are critical components of both subunit and certain inactivated vaccines because they induce specific immune responses that are more robust and long-lasting. A review of the history of coronavirus vaccine development demonstrates that only a few adjuvants, including aluminum salts, emulsions, and TLR agonists, have been formulated for the severe acute respiratory syndrome-associated coronavirus (SARS-CoV), Middle East respiratory syndrome-related coronavirus (MERS-CoV), and currently the SARS-CoV-2 vaccines in experimental and pre-clinical studies. However, there is still a lack of evidence regarding the effects of the adjuvants tested in coronavirus vaccines. This paper presents an overview of adjuvants that have been formulated in reported coronavirus vaccine studies, which should assist with the design and selection of adjuvants with optimal efficacy and safety profiles for COVID-19 vaccines.

112,946 views

176 citations

To evaluate the impact of sex on the specific vaccine candidate, we need to include both sexes as early as during the preclinical development stage and aim for a balanced sex ratio in clinical phase 1-3 trials. A detailed snapshot of immune responses to the vaccine can be achieved by frequent blood sampling following vaccination (1) and the application of various technologies (2). Here, we can evaluate responses to the vaccine on the transcriptome, epigenome and proteome level. Using bioinformatic tools (3), we may gain a comprehensive insight into multiple levels of immune responses that may be different in men and women (4). By comprehensively studying innate and adaptive immune responses in men and women, we may better understand how genetic or hormonal differences affect the number and functionality of immune cells.

Mini Review

08 January 2021

Sex Differences in Immunity: Implications for the Development of Novel Vaccines Against Emerging Pathogens

Anahita Fathi

, 1 more and

Christine Dahlke

10,843 views

43 citations

Original Research

04 November 2020

Adenoviral-Vectored Mayaro and Chikungunya Virus Vaccine Candidates Afford Partial Cross-Protection From Lethal Challenge in A129 Mouse Model

Rafael Kroon Campos

, 6 more and

Shannan L. Rossi

3,930 views

35 citations

Day 1–2: Following immediate availability of the virus genome sequence information, in silico design of ~20–30 constructs are initiated to allow for selection of optimally expressed antigens. The geneblocks and the primers arrive within 4–7 days following order placement from IDT after which cloning and transfection of the sequence confirmed constructs can be completed within 4 days. Small-scale expression of the transiently transfected cultures is completed within 5–7 days prior to affinity purification of the expressed clamped proteins using the culture supernatants. There is no need for pathogen-specific probes for the purification owing to the availability of human anti-clamp antibody embedded columns in-house. Purified proteins are analyzed in vitro for the expression yield, protein homogeneity on an SDS-PAGE, and the presence of the desired pre-fusion conformation by SEC and TEM (negative stain). The protein purification and in vitro analysis can be completed within 1–3 days.

Original Research

04 November 2020

Rapid Response Subunit Vaccine Design in the Absence of Structural Information

Danushka K. Wijesundara

, 6 more and

Keith J. Chappell

8,088 views

12 citations

The X axis indicates the index position of sequential peptides with single amino acid displacement. The Y axis indicates predicted binding affinity in standard deviation units for the protein. The red line shows the permuted average predicted MHC-IA and B (62 alleles) binding affinity by index position of sequential 9-mer peptides with single amino acid displacement. The blue line shows the permuted average predicted MHC-II DRB allele (24 most common human alleles) binding affinity of sequential 15-mer peptides. Orange lines show the predicted probability of B-cell receptor binding for an amino acid centered in each sequential 9-mer peptide. Low numbers for MHC data represent high binding affinity, whereas low numbers equate to high B cell receptor contact probability. Ribbons (red: MHC-I, blue: MHC-II) indicate the 10% highest predicted MHC affinity binding. Orange ribbons indicate the top 25% predicted probability B-cell binding. Horizontal dotted lines demarcate the top 5% of binding affinity for the protein (red MHC I, blue MHC II).

Original Research

28 October 2020

Immunoinformatic Analysis of SARS-CoV-2 Nucleocapsid Protein and Identification of COVID-19 Vaccine Targets

Sergio C. Oliveira

, 1 more and

E. Jane Homan

14,915 views

109 citations

Review

07 October 2020

The SARS-CoV-2 Spike Glycoprotein Biosynthesis, Structure, Function, and Antigenicity: Implications for the Design of Spike-Based Vaccine Immunogens

Liangwei Duan

, 4 more and

Hui Wang

The ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a grave threat to global public health and imposes a severe burden on the entire human society. Like other coronaviruses, the SARS-CoV-2 genome encodes spike (S) glycoproteins, which protrude from the surface of mature virions. The S glycoprotein plays essential roles in virus attachment, fusion and entry into the host cell. Surface location of the S glycoprotein renders it a direct target for host immune responses, making it the main target of neutralizing antibodies. In the light of its crucial roles in viral infection and adaptive immunity, the S protein is the focus of most vaccine strategies as well as therapeutic interventions. In this review, we highlight and describe the recent progress that has been made in the biosynthesis, structure, function, and antigenicity of the SARS-CoV-2 S glycoprotein, aiming to provide valuable insights into the design and development of the S protein-based vaccines as well as therapeutics.

154,142 views

382 citations