O-10554

The CoronaVac vaccine is widely used in Thailand to combat the coronavirus disease 2019 (COVID-19) pandemic. The limited immunogenicity of this vaccine is a concern, especially because of expanding delta variant outbreaks. A third boost may enhance antiviral immune responses.

This non-inferiority randomized controlled trial evaluated the immunogenicity and safety of an intradermal (ID) fractional third dose of AZD1222 vaccine compared with those of a standard intramuscular (IM) third dose. Participants were enrolled from August 9, 2021 to August 13, 2021 at Chulabhorn Hospital, Bangkok, Thailand. The eligibility criteria were age 18 years or older and prior two-dose Coronavac vaccination completed at least 2 months previously. Participants were randomly assigned to one of three groups by block randomization: (i) standard dose by IM administration (IM), (ii) 20% of the standard dose ID (ID1), or (iii) 40% of the standard dose ID (ID2). The primary endpoint was the geometric mean ratio of anti-receptor binding domain antibody in the ID1/ID2 vs. the IM groups 14 days post-vaccination.

A total of 125 participants were randomized (IM, n = 41; ID1, n = 41; and ID2, n = 43). One participant was lost to follow-up by day 14 post-vaccination in the ID1 group. The geometric mean ratio (95% confidence interval) of anti-receptor binding domain antibody was 0.94 (0.80-1.09) in the ID1 group and 1.28 (0.95-1.74) in the ID2 group. Immunogenicity in both ID groups met the non-inferiority criteria. Local adverse events were more common in the ID groups than in the IM group but were mostly mild to moderate in severity.

An ID fractional third dose of AZD1222 was non-inferior to a standard IM third dose among individuals previously vaccinated with CoronaVac. Adverse events associated with the ID fractional third dose included mild to moderate local site reactions. This vaccination strategy may help conserve vaccine supply.

Smallpox, caused by Variola virus (VARV), was eradicated in 1980; however, VARV bioterrorist threats still exist, necessitating readily available therapeutics. Current preparedness activities recognize the importance of oral antivirals and recommend therapeutics with different mechanisms of action. Monkeypox virus (MPXV) is closely related to VARV, causing a highly similar clinical human disease, and can be used as a surrogate for smallpox antiviral testing. The prairie dog MPXV model has been characterized and used to study the efficacy of antipoxvirus therapeutics, including recently approved TPOXX (tecovirimat). Brincidofovir (BCV; CMX001) has shown antiviral activity against double-stranded DNA viruses, including poxviruses. To determine the exposure of BCV following oral administration to prairie dogs, a pharmacokinetics (PK) study was performed. Analysis of BCV plasma concentrations indicated variability, conceivably due to the outbred nature of the animals. To determine BCV efficacy in the MPXV prairie dog model, groups of animals were intranasally challenged with 9 × 10⁵ plaque-forming units (PFU; 90% lethal dose [LD₉₀]) of MPXV on inoculation day 0 (ID0). Animals were divided into groups based on the first day of BCV treatment relative to inoculation day (ID-1, ID0, or ID1). A trend in efficacy was noted dependent upon treatment initiation (57% on ID-1, 43% on ID0, and 29% on ID1) but was lower than demonstrated in other animal models. Analysis of the PK data indicated that BCV plasma exposure (maximum concentration [C_max]) and the time of the last quantifiable concentration (AUC_last) were lower than in other animal models administered the same doses, indicating that suboptimal BCV exposure may explain the lower protective effect on survival.IMPORTANCE Preparedness activities against highly transmissible viruses with high mortality rates have been highlighted during the ongoing coronavirus disease 2019 (COVID-19) pandemic. Smallpox, caused by variola virus (VARV) infection, is highly transmissible, with an estimated 30% mortality. Through an intensive vaccination campaign, smallpox was declared eradicated in 1980, and routine smallpox vaccination of individuals ceased. Today's current population has little/no immunity against VARV. If smallpox were to reemerge, the worldwide results would be devastating. Recent FDA approval of one smallpox antiviral (tecovirimat) was a successful step in biothreat preparedness; however, orthopoxviruses can become resistant to treatment, suggesting the need for multiple therapeutics. Our paper details the efficacy of the investigational smallpox drug brincidofovir in a monkeypox virus (MPXV) animal model. Since brincidofovir has not been tested in vivo against smallpox, studies with the related virus MPXV are critical in understanding whether it would be protective in the event of a smallpox outbreak.