Adenovirus-based vaccines-a platform for pandemic preparedness against emerging viral pathogens

Abstract

Zoonotic viruses continually pose a pandemic threat. Infection of humans with viruses for which we typically have little or no prior immunity can result in epidemics with high morbidity and mortality. These epidemics can have public health and economic impact and can exacerbate civil unrest or political instability. Changes in human behavior in the past few decades-increased global travel, farming intensification, the exotic animal trade, and the impact of global warming on animal migratory patterns, habitats, and ecosystems-contribute to the increased frequency of cross-species transmission events. Investing in the pre-clinical advancement of vaccine candidates against diverse emerging viral threats is crucial for pandemic preparedness. Replication-defective adenoviral (Ad) vectors have demonstrated their utility as an outbreak-responsive vaccine platform during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Ad vectors are easy to engineer; are amenable to rapid, inexpensive manufacturing; are relatively safe and immunogenic in humans; and, importantly, do not require specialized cold-chain storage, making them an ideal platform for equitable global distribution or stockpiling. In this review, we discuss the progress in applying Ad-based vaccines against emerging viruses and summarize their global safety profile, as reflected by their widespread geographic use during the SARS-CoV-2 pandemic.

Keywords: adenovirus; emerging; outbreak; pandemic; pathogen; vaccine; vector; virus.

Graphical abstract

Figure 1

Vaccine platforms for outbreak pathogens Schematic diagram showing the range of different platforms that can be used for vaccine development. (A) Nucleic-acid-based vaccines (i.e., DNA or mRNA) encode the vaccine antigen target sequence, allowing for transgene expression in vivo. These vaccines facilitate both MHC class I antigen presentation from cells at the site of injection and MHC class II antigen presentation by APCs. (B) Similarly, viral-vectored vaccines (i.e., Ads) can also encode the transgene antigen sequence or display peptide antigen on the capsid exterior. These vectors allow for in vivo expression and antigen processing via MHC class I and class II. (C) Virus-like-particles (VLPs) or protein-based vaccines are processed in a similar manner to inactivated platforms. (D) Inactivated vaccine platforms are largely scavenged by APCs, resulting in MHC class II presentation, although cross-presentation in dendritic cells (DCs) can facilitate MHC class I presentation. As live attenuated vaccines can infect respiratory epithelia, they can also present antigen via MHC class I. Figure created with BioRender.com.

Figure 2

Schematic diagram outlining the antigen-presentation mechanisms used by Ad-based vaccines (1) Ad-vaccine is taken up by muscle cells or antigen-presenting cells (APCs) at the site of injection or following trafficking to draining lymph nodes (dLNs). (2) In parenchymal cells (i.e., muscle), uptake can be mediated by endocytosis. (3) Ad vaccine escapes from the endosome. (4) Partially disassembled Ad capsids traffic to the nucleus using the microtubule network. (5) Once in the nucleus, the encoded vaccine transgene antigen is transcribed. (6) mRNA corresponding to the encoded transgene antigen is exported to the cytoplasm and is translated into protein. (7) Antigen is expressed, and some antigen is degraded by the proteasome. (8) Depending on the antigen design, glycoproteins that normally traffic to the plasma membrane will follow this path and can potentially be recognized by Abs, including those capable of Fc-mediated effector function. (9) Degraded peptide antigen can be loaded onto MHC class I for direct presentation to CD8⁺ T cells. (10) Secreted antigens can be released into the extracellular space or apoptosis of transgene-expressing cells can also facilitate antigen release. Extracellular (exogenous) antigen can be scavenged by macrophages or other APCs at the site of injection. (11) Antigen fragments arriving in the dLN are phagocytosed by professional APCs and peptides processed and presented to T cells via appropriate MHC molecules. Figure created with BioRender.com.

Figure 3

Schematic diagrams of the structure of several emerging viruses identified as priority pathogens by the WHO (A) A general structure of the Filoviridae family, highlighting antigen targets that have been employed in vaccine design. (B) Structure of the Arenaviridae family, showing antigen targets for vaccine development. (C) A schematic structure for viruses from the families Nairoviridae, Hantaviridae, or Phenuiviridae, order Bunyavirales, again showing vaccine target antigens. (D) Diagram showing the general structure of Zika virus, a member of the Flaviviridae family, and major targets for vaccine design. Figure created with BioRender.com.