Altering the mRNA-1273 dosing interval impacts the kinetics, quality, and magnitude of immune responses in mice.

For a vaccine to achieve durable immunity and optimal efficacy, many require a multi-dose primary vaccination schedule that acts to first "prime" naive immune systems and then "boost" initial immune responses by repeated immunizations (ie, prime-boost regimens). In the context of the global coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 2-dose primary vaccination regimens were often selected with short intervals between doses to provide rapid protection while still inducing robust immunity. However, emerging post-authorization evidence has suggested that longer intervals between doses 1 and 2 for SARS-CoV-2 vaccines may positively impact robustness and durability of immune responses. Here, the dosing interval for mRNA-1273, a messenger RNA based SARS-CoV-2 vaccine administered on a 2-dose primary schedule with 4 weeks between doses, was evaluated in mice by varying the dose interval between 1 and 8 weeks and examining immune responses through 24 weeks after dose 2. A dosing interval of 6 to 8 weeks generated the highest level of antigen-specific serum immunoglobulin G binding antibody titers. Differences in binding antibody titers between mRNA-1273 1 µg and 10 µg decreased over time for dosing intervals of ≥4 weeks, suggesting a potential dose-sparing effect. Longer intervals (≥4 weeks) also increased antibody-dependent cellular cytotoxicity activity and numbers of antibody-secreting cells (including long-lived plasma cells) after the second dose. An interval of 6 to 8 weeks elicited the strongest CD8+ T-cell responses, while an interval of 3 weeks elicited the strongest CD4+ T-cell response. Overall, these results suggest that in a non-pandemic setting, a longer interval (≥6 weeks) between the doses of the primary series for mRNA-1273 may induce more durable immune responses.

Combating Viral Diseases in the Era of Systems Medicine.

Viruses can cause many diseases resulting in disabilities and death. Fortunately, advances in systems medicine enable the development of effective therapies for treating viral diseases, of vaccines to prevent viral infections, as well as of diagnostic tools to mitigate the risk and reduce the death toll. Characterizing the SARS-CoV-2 gene sequence and the role of its spike protein in infection informs development of small molecule drugs, antibodies, and vaccines to combat infection and complication, as well as to end the pandemic. Drug repurposing of small molecule drugs is a viable strategy to combat viral diseases; the key concepts include (1) linking a drug candidate's pharmacological network to its pharmacodynamic response in patients; (2) linking a drug candidate's physicochemical properties to its pharmacokinetic characteristics; and (3) optimizing the safe and effective dosing regimen within its therapeutic window. Computational integration of drug-induced signaling pathways with clinical outcomes is useful to inform selection of potential drug candidates with respect to safety and effectiveness. Key pharmacokinetic and pharmacodynamic principles for computational optimization of drug development include a drug candidate's Cminss/IC95 ratio, pharmacokinetic characteristics, and systemic exposure-response relationship, where Cminss is the trough concentration following multiple dosing. In summary, systems medicine approaches play a vital role in global success in combating viral diseases, including global real-time information sharing, development of test kits, drug repurposing, discovery and development of safe, effective therapies, detection of highly transmissible and deadly variants, and development of vaccines.