Abstract
As prophylactic vaccine adjuvants for infectious diseases, cyclic dinucleotides (CDNs) induce safe, potent, long-lasting humoral and cellular memory responses in the systemic and mucosal compartments. As therapeutic cancer vaccine adjuvants, CDNs induce potent anti-tumor immunity, including cytotoxic T cells and NK cells activation that achieve durable regression in multiple mouse models of tumors. Clinical trials are ongoing to fulfill the promise of CDNs (ClinicalTrials.gov: NCT02675439, NCT03010176, NCT03172936, and NCT03937141). However, in October 2018, the first clinical data with Merck’s CDN MK-1454 showed zero activity as a monotherapy in patients with solid tumors or lymphomas (NCT03010176). Lately, the clinical trial from Aduro’s CDN ADU-S100 monotherapy was also disappointing (NCT03172936). The emerging hurdle in CDN vaccine development calls for a timely re-evaluation of our understanding on CDN vaccine adjuvants. Here, we review the status of CDN vaccine adjuvant research, including their superior adjuvant activities, in vivo mode of action, and confounding factors that affect their efficacy in humans. Lastly, we discuss the strategies to overcome the hurdle and advance promising CDN adjuvants in humans.
Highlights
Vaccines, by no doubt, are one of the most crowning achievements of medical science
cyclic dinucleotides (CDNs) adjuvants induce balanced, durable humoral, cellular mucosal immune responses, and potent anti-tumor immunity that is highly desirable for vaccine protection from a broad spectrum of pathogens and cancers
To advance CDNs as a human vaccine and cancer adjuvants, more rigorous research to understand their mode of action in vivo are needed
Summary
By no doubt, are one of the most crowning achievements of medical science. The success of Edward Jenner’s smallpox vaccine and Louis Pasteur’s anthrax and rabies vaccines demonstrated the protection from the disease without transferring the disease itself. In the current COVID-19 vaccine development, most efforts aim to generate neutralizing antibodies against the SARS-CoV-2, rather than promoting the long-lived, potential cross-protective antiviral memory CD8+ T cells responses. CDN adjuvanted protein subunit vaccines generated mucosal immunity and protected mice from respiratory bacterial and viral infections such as influenza [8,10], Mycobacterium tuberculosis [11], anthrax [12], Klebsiella pneumoniae [13] and Streptococcus pneumoniae [4,5], Acinetobacter baumannii [14], and methicillin-resistant Staphylococcus aureus [15]. Superior to other vaccine adjuvants that induced biased immune responses (Table 1), CDNs produce balanced memory Th1/Th2/Th17 and cytotoxic CD8+ T cell [6,7,16,17]. CDNs possess a broad spectrum of vaccine adjuvant activities that are suited for protection from intracellular and extracellular pathogens [7,8,11,23]
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