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. 2023 Mar 24;211(3):269-279.
doi: 10.1093/cei/uxad003.

Transcriptomic response and immunological responses to chimpanzee adenovirus- and MVA viral-vectored vaccines for RSV in healthy adults

C Green  1   2 , J McGinley  1 , C Sande  1 , S Capone  3 , S Makvandi-Nejad  4 , A Vitelli  3 , L Silva-Reyes  1 , S Bibi  1 , C Otasowie  1 , D Sheerin  1 , A Thompson  1 , C Dold  1 , P Klenerman  5 , E Barnes  5 , L Dorrell  4 , C Rollier  1 , A Pollard  1 , D O'Connor  1
Affiliations

Transcriptomic response and immunological responses to chimpanzee adenovirus- and MVA viral-vectored vaccines for RSV in healthy adults

C Green et al. Clin Exp Immunol. .

Abstract

Cohorts of healthy younger adults (18-50yrs) and healthy older adults (60-75yrs) were immunized intramuscularly or intranasally with an adenovirus-vectored RSV vaccine (PanAd3-RSV) as a prime dose and boosted with PanAd3-RSV or a poxvirus-vectored vaccine (MVA-RSV) encoding the same insert. Whole blood gene expression was measured at baseline, 3- and 7-days post vaccination. Intramuscular prime vaccination with PanAd3-RSV induced differential expression of 643 genes (DEGs, FDR < 0.05). Intranasal prime vaccination with PanAd3-RSV did not induce any differentially expressed genes (DEGs) in blood samples at 3 days post vaccination. Intranasally primed participants showed greater numbers of DEGS on boosting than intramuscularly primed participants. The most highly enriched biological processes related to DEGs after both prime and boost vaccination were type-1 interferon related pathways, lymphocytic and humoral immune responses.

Keywords: RSV; antibodies; human trials; transcriptomics; vaccine; viral vectors.

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Conflict of interest statement

A.P. has previously conducted clinical trials of vaccines on behalf of Oxford University funded by GlaxoSmithKline Biologicals SA and ReiThera S.r.l, but does not receive any personal payments from them. A.P. is chair of the UK Department of Health’s (DH) Joint Committee on Vaccination and Immunisation (JCVI), but the views expressed in this manuscript do not necessarily represent the views of JCVI or DH. A.V. is a named inventor on patent applications covering RSV antigen expression system (WO 2012/089833). The remaining authors declare they have no competing interests.

Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
Volcano plot illustrations of early transcriptional responses to RSV vaccination. A: Transcriptional response of N = 21 volunteers who received PanAd3-RSV prime vaccination by IM injection measured 3-days after vaccination. B: Transcriptional response of N = 21 volunteers who received PanAd3-RSV prime vaccination by IM injection measured 7 days after vaccination. C: Transcriptional response of N = 11 volunteers who received MVA-RSV boost vaccination by IM injection after being primed with IM PanAd3-RSV measured 3 days after boost vaccination. D: Transcriptional response of N = 10 volunteers who received MVA-RSV boost vaccination by IM injection after IN PanAd3 prime vaccination measured 3-days after boost vaccination. E: Transcriptional response N = 10 volunteers who received MVA-RSV boost vaccination by IM injection after IN priming with PanAd3-RSV measured 7 days after boost vaccination. Red dots denote significantly differentially expressed probes (FDR < 0.05, log2 fold change > 0.26), blue dots significantly differentially expressed probes with fold change < 1.2, green dots indicate genes with a log2 fold change > 0.26 but which are not significantly differentially expressed. Horizontal dotted lines represent FDR cutoffs, vertical dotted lines represent log2 fold change cutoffs. (F) Agreement plot of differentially expressed probes 3 days after IM PanAd3-RSV prime or IM MVA-RSV boost vaccination (IN primed volunteers). Plot of the log2 adjusted fold changes of all shared differentially expressed genes 3 days after intramuscular priming with PanAd3-RSV and intramuscular boosting with MVA-RSV in participants primed intramuscularly. Points coloured in purple represent genes that are downregulated post both vaccinations. Blue points are genes that are upregulated after both vaccinations. No differentially expressed genes were downregulated in response to one vaccination and upregulated in response to another.
Figure 2.
Figure 2.
Gene set enrichment analysis of biological processes of the response to prime vaccination three and seven days after vaccination. Gene enrichment analysis for terms relating to biological processes was performed on the ranked list of all probes on the array at 3 (A) and 7 days (B) post prime vaccination and 3 (C) and 7 days (D) post boost vaccination by MVA-RSV in participants primed intranasally. Most significantly enriched terms are ranked by enrichment score. Dots are coloured based on the FDR of the associated term. Size of dots is based on the number of genes associated with that term. FDR <0.05 was used. Early transcriptional changes correlate with vaccine responses in younger adults
Figure 3.
Figure 3.
(A–F) IFI27, MX1, OAS1, and RSAD2 are significantly differentially expressed in older adult grouping after prime vaccination with PanAd Titres of genes determined to be relevant to the generation of immunological outcomes such as neutralising antibody response were measured in older adults by qPCR. Results are presented as ddCT between day of vaccination and 28 days post vaccination. Asterisk indicates differential expression of that gene compared with baseline levels (P < 0.05), genes after prime vaccination are coloured in red while genes after boost are coloured in blue.
Figure 4
Figure 4
(A–F) Correlation between gene expression and neutralising antibody in older adults Pearson correlation between changes in gene expression 3 days post prime vaccination in older adults as measured by rt-qPCR and log 2-fold change in RSV neutralizing antibody measured at 28 days post vaccination. Grey area indicates confidence interval for the data. Line represents degree of correlation between fold change in gene expression and fold change in neutralizing antibody.
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