Immunogenicity and safety of an ORF7-deficient skin- attenuated and neuro-attenuated live vaccine for varicella: a randomised, double-blind, controlled, phase 2atrial

Background The Oka varicella vaccine strain remains neurovirulent and can establish lifelong latent infection, raising safety concerns about vaccine-related herpes zoster. In this study, we aimed to evaluate the immunogenicity and safety of a skin-attenuated and neuro-attenuated varicella vaccine candidate (v7D vaccine). Methods We did this randomised, double-blind, controlled, phase 2a clinical trial in Jiangsu, China. Healthy children aged 3-12 years with no history of varicella infection or vaccination were enrolled and randomly assigned (1:1:1:1) to receive a single subcutaneous injection of the v7D vaccine at 3<middle dot>3 log10 10 plaque forming units (PFU; low-dose v7D group), 3<middle dot>9 log10 10 PFU (medium-dose v7D group), and 4<middle dot>2 log10 10 PFU (high-dose v7D group), or the positive control varicella vaccine (vOka vaccine group). All the participants, laboratory personnel, and investigators other than the vaccine preparation and management staff were masked to the vaccine allocation. The primary outcome was assessment of the geometric mean titres (GMTs) and seroconversion rates of anti-varicella zoster virus immunoglobulin G (IgG) induced by different dose groups of v7D vaccine at 0, 42, 60, and 90 days after vaccination in the per-protocol set for humoral immune response analysis. Safety was a secondary outcome, focusing on adverse events within 42 days post-vaccination, and serious adverse events within 6 months after vaccination. This study was registered on Chinese Clinical Trial Registry, ChiCTR2000034434. Findings On Aug 18-21, 2020, 842 eligible volunteers were enrolled and randomly assigned treatment. After three participants withdrew, 839 received a low dose (n=211), middle dose (n=210), or high dose (n=210) of v7D vaccine, or the vOka vaccine (n=208). In the per-protocol set for humoral immune response analysis, the anti-varicella zoster virus IgG antibody response was highest at day 90. At day 90, the seroconversion rates of the low-dose, medium- dose, and high-dose groups of v7D vaccine and the positive control vOka vaccine group were 100<middle dot>0% (95% CI 95<middle dot>8-100<middle dot>0; 87 of 87 participants), 98<middle dot>9% (93<middle dot>8-100<middle dot>0; 87 of 88 participants), 97<middle dot>8% (92<middle dot>4-99<middle dot>7; 91 of 93 participants), and 96<middle dot>4% (89<middle dot>8-99<middle dot>2; 80 of 83 participants), respectively; the GMTs corresponded to values of 30<middle dot>8 (95% CI 26<middle dot>2-36<middle dot>0), 31<middle dot>3 (26<middle dot>7-36<middle dot>6), 28<middle dot>2 (23<middle dot>9-33<middle dot>2), and 38<middle dot>5 (31<middle dot>7-46<middle dot>7). The v7D vaccine, at low dose and medium dose, elicited a humoral immune response similar to that of the vOka vaccine. However, the high-dose v7D vaccine induced a marginally lower GMT compared with the vOka vaccine at day 90 (p=0<middle dot>027). In the per-protocol set, the three dose groups of the v7D vaccine induced a similar humoral immune response at each timepoint, with no statistically significant differences. The incidence of adverse reactions in the low-dose, medium-dose, and high-dose groups of v7D vaccine was significantly lower than that in the vOka vaccine group (17% [35 of 211 participants], 20% [41 of 210 participants], and 13% [27 of 210 participants] vs 24% [50 of 208 participants], respectively; p=0<middle dot>025), especially local adverse reactions (10% [22 of 211 participants], 14% [30 of 210 participants] and 9% [18 of 210 participants] vs 18% [38 of 208 participants], respectively; p=0<middle dot>016). None of the serious adverse events were vaccine related. Interpretation The three dose groups of the candidate v7D vaccine exhibit similar humoral immunogenicity to the vOka vaccine and are well tolerated. These findings encourage further investigations on two-dose vaccination schedules, efficacy, and the potential safety benefit of v7D vaccine in the future.