Protein/AS01B vaccination elicits stronger, more Th2-skewed antigen-specific human T follicular helper cell responses than heterologous viral vectors

Nielsen, Carolyn M.; Ogbe, Ane; Pedroza-Pacheco, Isabela; Doeleman, Susanne E.; Chen, Yue; Silk, Sarah E.; Barrett, Jordan R.; Elias, Sean C.; Miura, Kazutoyo; Diouf, Ababacar; Bardelli, Martino; Dabbs, Rebecca A.; Barfod, Lea; Long, Carole A.; Haynes, Barton F.; Payne, Ruth; Minassian, Angela M.; Bradley, Todd; Draper, Simon J.; Borrow, Persephone

doi:10.1016/j.xcrm.2021.100207

Cited by 32 publications

(56 citation statements)

References 61 publications

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“…Other studies in convalescent cohorts have linked a CCR6+ Th-17 cTfh phenotype with reduced disease severity (49). Similar to others (44, 50), we found antigen-specific CD4+T cells following vaccination were mostly a CCR6+ CXCR3- Th-17 phenotype. We did not find SARS-CoV-2 spike-specific CD4+ T cells biased towards any chemokine-expressing sub-population 6 months after vaccination, possibly reflecting the longer duration between vaccination and analysis than in other studies.…”

Section: Discussionsupporting

confidence: 90%

Durability of ChAdOx1 nCov-19 (AZD1222) vaccination in people living with HIV - responses to SARS-CoV-2, variants of concern and circulating coronaviruses

Ogbe

Pace

Bittaye

et al. 2021

Preprint

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Duration of protection from SARS-CoV-2 infection in people with HIV (PWH) following vaccination is unclear. In a sub-study of the phase 2/3 the COV002 trial (NCT04400838), 54 HIV positive male participants on antiretroviral therapy (undetectable viral loads, CD4+ T cells >350 cells/ul) received two doses of ChAdOx1 nCoV-19 (AZD1222) 4-6 weeks apart and were followed for 6 months. Responses to vaccination were determined by serology (IgG ELISA and MesoScale Discovery (MSD)), neutralisation, ACE-2 inhibition, gamma interferon ELISpot, activation-induced marker (AIM) assay and T cell proliferation. We show that 6 months after vaccination the majority of measurable immune responses were greater than pre-vaccination baseline, but with evidence of a decline in both humoral and cell mediated immunity. There was, however, no significant difference compared to a cohort of HIV-uninfected individuals vaccinated with the same regimen. Responses to the variants of concern were detectable, although were lower than wild type. Pre-existing cross-reactive T cell responses to SARS-CoV-2 spike were associated with greater post-vaccine immunity and correlated with prior exposure to beta coronaviruses. These data support the on-going policy to vaccinate PWH against SARS-CoV-2, and underpin the need for long-term monitoring of responses after vaccination.

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Section: Discussionsupporting

confidence: 90%

Durability of ChAdOx1 nCov-19 (AZD1222) vaccination in people living with HIV - responses to SARS-CoV-2, variants of concern and circulating coronaviruses

Ogbe

Pace

Bittaye

et al. 2021

Preprint

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“…To determine if similarly high recall responses might be found in RH5 vaccinees from the VAC057 clinical trial, peptides representing three of the N-terminal clusters (clusters 3, 4, and 6) were also assessed in HLA-matched donors from this study. Notably, RH5 was delivered via viral vector in VAC057 and differences in immunogenicity between recombinant and viral vectored RH5 have been shown ( 12 ). Ex vivo assessments of IFN-γ T cell recall responses were conducted using donor samples collected 14 days after the VAC057 vaccinees had received a single dose (5x10 10 viral particles) of ChAd63 RH5 ( Table S21 ).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, these cells can play a direct role in enabling the killing of activated phagocytes that have phagocytosed infected erythrocytes (11). Antigen-specific T cell responses have also been observed against viral-vectored malaria blood stage antigens in humans (12)(13)(14)(15)(16)(17). Humoral responses induced by viral vector vaccines expressing malaria-specific and non-malaria antigens accompany induction of antigen-specific follicular T helper (Tfh) cells (12,18,19).…”

Section: Introductionmentioning

confidence: 99%

“…Antigen-specific T cell responses have also been observed against viral-vectored malaria blood stage antigens in humans (12)(13)(14)(15)(16)(17). Humoral responses induced by viral vector vaccines expressing malaria-specific and non-malaria antigens accompany induction of antigen-specific follicular T helper (Tfh) cells (12,18,19). For example, Tfh cells enhance memory and plasma B cell generation following influenza vaccination (20,21).…”

Section: Introductionmentioning

confidence: 99%

“…For example, Tfh cells enhance memory and plasma B cell generation following influenza vaccination ( 20 , 21 ). Further, frequencies of antigen-specific Tfh cells following vaccination with a malaria blood stage antigen RH5 correlate with peak anti-specific IgG concentration, frequency of antigen-specific memory B cells, and purified IgG in vitro neutralization activity ( 12 ). These findings strongly indicate that evaluation of T cell epitope content in vaccine targets is a critical step in vaccine design and optimization.…”

Section: Introductionmentioning

confidence: 99%

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Identification and Immune Assessment of T Cell Epitopes in Five Plasmodium falciparum Blood Stage Antigens to Facilitate Vaccine Candidate Selection and Optimization

et al. 2021

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The hurdles to effective blood stage malaria vaccine design include immune evasion tactics used by the parasite such as redundant invasion pathways and antigen variation among circulating parasite strains. While blood stage malaria vaccine development primarily focuses on eliciting optimal humoral responses capable of blocking erythrocyte invasion, clinically-tested Plasmodium falciparum (Pf) vaccines have not elicited sterile protection, in part due to the dramatically high levels of antibody needed. Recent development efforts with non-redundant, conserved blood stage antigens suggest both high antibody titer and rapid antibody binding kinetics are important efficacy factors. Based on the central role of helper CD4 T cells in development of strong, protective immune responses, we systematically analyzed the class II epitope content in five leading Pf blood stage antigens (RH5, CyRPA, RIPR, AMA1 and EBA175) using in silico, in vitro, and ex vivo methodologies. We employed in silico T cell epitope analysis to enable identification of 67 HLA-restricted class II epitope clusters predicted to bind a panel of nine HLA-DRB1 alleles. We assessed a subset of these for HLA-DRB1 allele binding in vitro, to verify the in silico predictions. All clusters assessed (40 clusters represented by 46 peptides) bound at least two HLA-DR alleles in vitro. The overall epitope prediction to in vitro HLA-DRB1 allele binding accuracy was 71%. Utilizing the set of RH5 class II epitope clusters (10 clusters represented by 12 peptides), we assessed stimulation of T cells collected from HLA-matched RH5 vaccinees using an IFN-γ T cell recall assay. All clusters demonstrated positive recall responses, with the highest responses – by percentage of responders and response magnitude – associated with clusters located in the N-terminal region of RH5. Finally, a statistically significant correlation between in silico epitope predictions and ex vivo IFN-γ recall response was found when accounting for HLA-DR matches between the epitope predictions and donor HLA phenotypes. This is the first comprehensive analysis of class II epitope content in RH5, CyRPA, RIPR, AMA1 and EBA175 accompanied by in vitro HLA binding validation for all five proteins and ex vivo T cell response confirmation for RH5.

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Improved Synthesis of D‐Isoglutamine: Rapid Access to Desmuramyl Analogues of Muramyl Dipeptide for the Activation of Intracellular NOD2 Receptor and Vaccine Adjuvant Applications

Khan

Khanam

et al. 2021

Eur J Org Chem

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Muramyl dipeptide (MDP) -the smallest immunomodulatory unit of bacterial peptidoglycan -has adjuvant activity and triggers the innate immune system against bacterial and viral infections. The inherited drawbacks of MDP, such as pyrogenicity and poor macrophage penetration, can be resolved by structural modifications, thereby improving its pharmacological profile and adjuvant activity. Herein, several desmuramyl analogues of MDP were designed by replacing the carbohydrate fragment (MurNAc) of the parent molecule with an immunomodulatory xanthine scaffold. The LÀ D configurations of the pharmacophoric dipeptidyl moiety were conserved and alkyl chains of moderate length were introduced at isoglutamine to enhance their cellular uptake. The synthesis of these analogues features a novel synthetic route for D-isoglutamine fragment with an overall yield of > 50 % in ten to eleven steps. This sufficiently flexible approach provides rapid access to desmuramyl analogues of MDP on a gram scale, which can help accelerate the development of novel NOD2 agonists and immunoadjuvants.

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Protein/AS01B vaccination elicits stronger, more Th2-skewed antigen-specific human T follicular helper cell responses than heterologous viral vectors

Cited by 32 publications

References 61 publications

Durability of ChAdOx1 nCov-19 (AZD1222) vaccination in people living with HIV - responses to SARS-CoV-2, variants of concern and circulating coronaviruses

Durability of ChAdOx1 nCov-19 (AZD1222) vaccination in people living with HIV - responses to SARS-CoV-2, variants of concern and circulating coronaviruses

Identification and Immune Assessment of T Cell Epitopes in Five Plasmodium falciparum Blood Stage Antigens to Facilitate Vaccine Candidate Selection and Optimization

Improved Synthesis of D‐Isoglutamine: Rapid Access to Desmuramyl Analogues of Muramyl Dipeptide for the Activation of Intracellular NOD2 Receptor and Vaccine Adjuvant Applications

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