Adenoviral vector vaccines were among the first vaccines deployed at scale during the COVID-19 pandemic. Their rapid development, relatively low manufacturing cost, straightforward scalability and stability at standard refrigeration temperatures supported global access, including in low- and middle-income settings. More than 3 billion doses were produced during the first pandemic year, and adenoviral vector vaccines are estimated to have saved millions of lives.
Despite this success, large-scale deployment also identified areas for improvement. Compared with mRNA platforms, adenoviral vectors may induce lower antibody responses in homologous prime–boost schedules, in part because pre-existing or vaccine-induced anti-vector immunity can reduce vector entry and transgene expression. In addition, the rare but serious syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) highlighted the need to better understand and mitigate interactions between adenoviral capsids, platelet factor 4 (PF4) and the host immune system.
This review outlines several strategies for next-generation adenoviral vector vaccines. These include selecting rare human or non-human adenovirus serotypes with low population seroprevalence, engineering vectors to evade anti-vector immunity or improve antigen expression, and modifying or shielding capsid proteins to reduce undesirable interactions, including PF4 binding. Approaches such as single-cycle vectors and capsid display may also enhance immune responses, while high-capacity vectors could enable multivalent vaccines or the co-delivery of immunomodulatory factors.
Alternative delivery routes may increase the potential and usage even more. Intranasal, aerosolised and oral adenoviral vaccines can stimulate mucosal immunity, including secretory IgA and tissue-resident memory T cells, which may be important for reducing infection and transmission at respiratory and gastrointestinal barrier sites. Microneedle delivery may improve thermostability, reduce the required dose and lessen anti-vector immune responses.
Adenoviral vectors remain particularly valuable for pandemic preparedness, endemic infectious diseases, and potentially therapeutic cancer vaccination because of their modular design, rapid adaptability, manufacturing feasibility and strong capacity to induce CD8 T-cell responses. The next generation of vectors will need to combine these established strengths with improved humoral immunogenicity, better reusability, and carefully engineered safety profiles.
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