Papers of the Month – 2024

April, 2024

NPJ Vaccines. 2024 Apr 6;9(1):74. doi: 10.1038/s41541-024-00862-8. PMID: 38582771; PMCID: PMC10998906.

Del Moral-Sánchez I, Wee EG, Xian Y, Lee WH, Allen JD, Torrents de la Peña A, Fróes Rocha R, Ferguson J, León AN, Koekkoek S, Schermer EE, Burger JA, Kumar S, Zwolsman R, Brinkkemper M, Aartse A, Eggink D, Han J, Yuan M, Crispin M, Ozorowski G, Ward AB, Wilson IA, Hanke T, Sliepen K, Sanders RW.

Recombinant native-like HIV-1 envelope glycoprotein (Env) trimers are used in candidate vaccines aimed at inducing broadly neutralizing antibodies. While state-of-the-art SOSIP or single-chain Env designs can be expressed as native-like trimers, undesired monomers, dimers and malformed trimers that elicit non-neutralizing antibodies are also formed, implying that these designs could benefit from further modifications for gene-based vaccination approaches. Here, we describe the triple tandem trimer (TTT) design, in which three Env protomers are genetically linked in a single open reading frame and express as native-like trimers. Viral vectored Env TTT induced similar neutralization titers but with a higher proportion of trimer-specific responses. The TTT design was also applied to generate influenza hemagglutinin (HA) trimers without the need for trimerization domains. Additionally, we used TTT to generate well-folded chimeric Env and HA trimers that harbor protomers from three different strains. In summary, the TTT design is a useful platform for the design of HIV-1 Env and influenza HA immunogens for a multitude of vaccination strategies.

March, 2024

Nat Immunol. 2024 Mar;25(3):418-431. doi: 10.1038/s41590-023-01739-z. Epub 2024 Jan 15. Erratum in: Nat Immunol. 2024 Feb 1;: PMID: 38225437.

Tran KA, Pernet E, Sadeghi M, Downey J, Chronopoulos J, Lapshina E, Tsai O, Kaufmann E, Ding J, Divangahi M.

After a century of using the Bacillus Calmette-Guérin (BCG) vaccine, our understanding of its ability to provide protection against homologous (Mycobacterium tuberculosis) or heterologous (for example, influenza virus) infections remains limited. Here we show that systemic (intravenous) BCG vaccination provides significant protection against subsequent influenza A virus infection in mice. We further demonstrate that the BCG-mediated cross-protection against influenza A virus is largely due to the enrichment of conventional CD4+ effector CX3CR1hi memory αβ T cells in the circulation and lung parenchyma. Importantly, pulmonary CX3CR1hi T cells limit early viral infection in an antigen-independent manner via potent interferon-γ production, which subsequently enhances long-term antimicrobial activity of alveolar macrophages. These results offer insight into the unknown mechanism by which BCG has persistently displayed broad protection against non-tuberculosis infections via cross-talk between adaptive and innate memory responses.

February, 2024

PMID: 38351001 PMCID: PMC10864359 DOI: 10.1038/s41467-024-45480-z

A General Computational Design Strategy for Stabilizing Viral Class I Fusion Proteins
Karen J Gonzalez 1, Jiachen Huang 2 3, Miria F Criado 3 4, Avik Banerjee 2 3, Stephen M Tompkins 2 3, Jarrod J Mousa 2 3 5, Eva-Maria Strauch 6 7 8

Many pathogenic viruses rely on class I fusion proteins to fuse their viral membrane with the host cell membrane. To drive the fusion process, class I fusion proteins undergo an irreversible conformational change from a metastable prefusion state to an energetically more stable postfusion state. Mounting evidence underscores that antibodies targeting the prefusion conformation are the most potent, making it a compelling vaccine candidate. Here, we establish a computational design protocol that stabilizes the prefusion state while destabilizing the postfusion conformation. With this protocol, we stabilize the fusion proteins of the RSV, hMPV, and SARS-CoV-2 viruses, testing fewer than a handful of designs. The solved structures of these designed proteins from all three viruses evidence the atomic accuracy of our approach. Furthermore, the humoral response of the redesigned RSV F protein compares to that of the recently approved vaccine in a mouse model. While the parallel design of two conformations allows the identification of energetically sub-optimal positions for one conformation, our protocol also reveals diverse molecular strategies for stabilization. Given the clinical significance of viruses using class I fusion proteins, our algorithm can substantially contribute to vaccine development by reducing the time and resources needed to optimize these immunogens.

January, 2024

Sci Immunol. 2023 Dec 8;8(90):eadh0687. doi: 10.1126/sciimmunol.adh0687. Epub 2023 Dec 8. PMID: 38064569

Cai C, Gao Y, Adamo S, Rivera-Ballesteros O, Hansson L, Österborg A, Bergman P, Sandberg JK, Ljunggren HG, Björkström NK, Strålin K, Llewellyn-Lacey S, Price DA, Qin C, Grifoni A, Weiskopf D, Wherry EJ, Sette A, Aleman S, Buggert M.

T cells are critical for immune protection against severe COVID-19, but it has remained unclear whether repeated exposure to SARS-CoV-2 antigens delivered in the context of vaccination fuels T cell exhaustion or reshapes T cell functionality. Here, we sampled convalescent donors with a history of mild or severe COVID-19 before and after SARS-CoV-2 vaccination to profile the functional spectrum of hybrid T cell immunity. Using combined single-cell technologies and high-dimensional flow cytometry, we found that the frequencies and functional capabilities of spike-specific CD4+ and CD8+ T cells in previously infected individuals were enhanced by vaccination, despite concomitant increases in the expression of inhibitory receptors such as PD-1 and TIM3. In contrast, CD4+ and CD8+ T cells targeting non-spike proteins remained functionally static and waned over time, and only minimal effects were observed in healthy vaccinated donors experiencing breakthrough infections with SARS-CoV-2. Moreover, hybrid immunity was characterized by elevated expression of IFN-γ, which was linked with clonotype specificity in the CD8+ T cell lineage. Collectively, these findings identify a molecular hallmark of hybrid immunity and suggest that vaccination after infection is associated with cumulative immunological benefits over time, potentially conferring enhanced protection against subsequent episodes of COVID-19.

The International Society for Vaccines is an organization that engages, supports, and sustains the professional goals of a diverse membership in all areas relevant to vaccines and immunotherapeutics.  The ISV is a global not-for-profit organization that aims to encourage, establish, and promote the development and use of vaccines to prevent and control infectious and non-infectious diseases in animals and humans.  /  ISV Annual Congress