Effectiveness of a booster dose of aerosolized or intramuscular adenovirus type 5 vectored COVID-19 vaccine in adults: a multicenter, partially randomized, platform trial in China

Categories: Disease & Virus

March 27, 2025

Trial profile

Between May 23, 2023, and August 28, 2023, a total of 4089 eligible participants were equally randomized to receive a booster dose of aerosolized Ad5-nCoV via oral inhalation at 0.1 mL (IH Ad5-nCoV, n = 2039) or intramuscular injection of Ad5-nCoV at 0.5 mL (IM Ad5-nCoV, n = 2050). Additionally, 2008 participants who declined the booster vaccination but consented to participate in COVID-19 surveillance were enrolled as the control group. The final database was locked on March 05, 2024, after a 6-month follow-up period for participants in both the boosting groups and the control group. A total of 6097 participants were included in the final analysis (Fig. 1).

The median follow-up time for both vaccine groups and the control group was 168.0 days (IQR 168.0–180.0). The mean age of all participants was 53.1 years (SD 17.5; range 18–96), with 2902 (47.6%) individuals aged 18–54 years, and 3195 (52.4%) aged 55 years or older (Table 1). The demographic information for the two age groups is detailed in Table S1. Among the 6097 participants, 2821 (46.3%) were male, 1569 (25.7%) reported coexisting conditions and 4555 (74.7%) reported previous SARS-CoV-2 infection history at enrollment. Baseline characteristics were largely similar between the IH Ad5-nCoV and IM Ad5-nCoV groups, but differences were observed between both vaccine groups and the control group (p < 0.05). Specifically, participants in the control group were younger, with a higher proportion of female and SARS-CoV-2 infection history, a higher body mass index (BMI), and a lower proportion of coexisting conditions. In the immunogenicity subgroup, demographic characteristics were well-balanced between the IH Ad5-nCoV and IM Ad5-nCoV groups (Table S2).

Table 1 Demographic and baseline characteristics of the participants in the full analysis population

Effectiveness analysis

During the surveillance period, a total of 79 COVID-19 cases were confirmed, with 22 (23/1000 person-years) in the IH Ad5-nCoV group, 23 (24/1000 person-years) in the IM Ad5-nCoV group, and 34 (37/1000 person-years) in the control group. However, 5 COVID-19 cases (4 in the IH Ad5-nCoV group and 1 in the IM Ad5-nCoV group) were confirmed within 7 days post-vaccination and excluded from the analysis of the primary and secondary endpoints. As shown in Fig. 2, starting from 28 days post-vaccination, the cumulative COVID-19 incidence of both vaccine groups gradually showed differences compared to the control group.

**Fig. 2: Kaplan–Meier plot of vaccine effectiveness against COVID-19 in the full analysis population.**

In the full analysis population, from 14 days after the vaccination, 14 (15/1000 person-years) COVID-19 cases were confirmed in the IH Ad5-nCoV group, 19 (20/1000 person-years) cases were confirmed in the IM Ad5-nCoV group, and 34 (37/1000 person-years) cases were confirmed in the control group, which resulted in adjusted effectiveness of 52.3% (95% CI 10.4–74.6) for IH Ad5-nCoV and 37.2% for IM Ad5-nCoV (95% CI −11.2 to 64.5; Table 2). From 7 days after the vaccination, the adjusted effectiveness of IH Ad5-nCoV and IM Ad5-nCoV was 39.9% (95% CI −7.4 to 66.3) and 28.9% (95% CI −22.8 to 58.8), respectively. All COVID-19 cases confirmed during the surveillance period were symptomatic but mild, thus rendering an assessment of vaccine effectiveness against severe COVID-19 infeasible. Among the 18 successfully sequenced nucleic acid samples derived from COVID-19 endpoint cases, all were typed as Omicron variants, of which 9 (50.0%) were HK.3, 4 (22.2%) were EG.5.1.1, 3 (16.7%) were FY.3.1, 1 (5.6%) was FY.3, and 1 (5.6%) was GF.1.

Table 2 Vaccine effectiveness against COVID-19 in the full analysis population

The adjusted effectiveness of both vaccines in participants aged ≥55 years was numerically lower than that observed in those aged 18–54 years from 14 days after the vaccination, which was 34.5% [95% CI −116.3 to 80.2] vs. 60.2% [95% CI 14.8–81.4] in IH Ad5-nCoV group, and 10.8% [95% CI −166.9 to 70.2] vs. 45.9% [95% CI −7.5 to 72.8] in IM Ad5-nCoV group. Besides, numerically lower adjusted effectiveness of both vaccine groups was observed in participants with coexisting conditions compared to those without (IH Ad5-nCoV: 47.5% [95% CI −123.3 to 87.7] vs. 54.7% [95% CI 8.4–77.6]; IM Ad5-nCoV: 33.7 [95% CI −150.0 to 82.4] vs. 41.0% [95% CI −11.6 to 68.8]). Similarly, numerically lower adjusted effectiveness was found in those without SARS-CoV-2 infection history compared to those with (IH Ad5-nCoV: 50.6% [95% CI −199.6 to 91.9] vs. 52.4% [95% CI 6.8–75.6]; IM Ad5-nCoV: 5.0% [95% CI −328.2 to 78.9] vs. 40.3% [95% CI −11.2 to 67.9]; Table 2, Fig. S2).

Immunogenicity analysis

All participants in the immunogenicity subgroup (n = 121) donated blood samples at days 0 and 14, 118 (97.5%) and 115 (95.0%) of them donated blood samples at months 3 and 6, respectively. At baseline, 65.0% of participants in the IM Ad5-nCoV group and 75.4% of participants in the IH Ad5-nCoV group exhibited an inhibition of ≥50% against wild-type SARS-CoV-2. Furthermore, 40.0–45.0% of participants in the IM Ad5-nCoV group and 50.8–59.0% of participants in the IH Ad5-nCoV group demonstrated inhibition of ≥50% against BA.4, BA.5, and BF.7 variants. However, only 25.0% of participants in the IM Ad5-nCoV group and 36.1% of participants in the IH Ad5-nCoV group showed inhibition of ≥50% against the XBB.1 variant (Fig. 3). 14 days after the booster dose, both vaccines elicited even higher ACE2-RBD binding inhibition against wild-type SARS-CoV-2. Specifically, 95.0% of participants in the IM Ad5-nCoV group and 88.5% of participants in the IH Ad5-nCoV group achieved an inhibition of ≥50%. 6 months post- booster, the proportion of ACE2-RBD binding inhibition ≥50% in the IM Ad5-nCoV group declined significantly to 64.9%, whereas it remained high at 86.2% in the IH Ad5-nCoV group. Regarding the XBB.1 variant, the proportion of ACE2-RBD binding inhibition ≥50% peaked at 14 days in the IM Ad5-nCoV group, with 63.3% of participants achieving this level. In contrast, for the IH Ad5-nCoV group, the peak of ACE2-RBD binding inhibition ≥50% was observed at 3 months post-booster, with 70.0% of participants meeting the criterion. Furthermore, the stratified results based on SARS-CoV-2 infection history indicated that compared to participants with a history of infection, those without SARS-CoV-2 infection history had numerically lower baseline ACE2-RBD binding inhibition against wild-type SARS-CoV-2, BA.5 and XBB.1 variants but exhibited a greater increase 14 days after booster in both vaccine groups (Fig. S5).

**Fig. 3: ACE2-RBD binding inhibition (%) against spikes of SARS-CoV-2 and variants in serum before and after the booster vaccination.**

Pseudovirus neutralization results revealed that both vaccine groups exhibited relatively high geometric mean titers (GMTs) of antibody at baseline against wild-type SARS-CoV-2 (IH Ad5-nCoV: 550.4; IM Ad5-nCoV: 411.0) and BA.4/5 (IH Ad5-nCoV: 451.9; IM Ad5-nCoV: 300.9). After vaccination, pseudovirus neutralization antibody titers against wild-type SARS-CoV-2 in the IH Ad5-nCoV group moderately increased from 14 days and peaked at 3 months after vaccination, then slightly declined at 6 months, with GMTs of 796.9 (95% CI 635.6–999.1), 1026.2 (95% CI 792.7–1328.6) and 880.9 (95% CI 700.9–1107.2), respectively (Fig. 4). Compared with the GMTs of pseudovirus neutralization antibodies against wild-type SARS-CoV-2 in the IH Ad5-nCoV group, those in the IM Ad5-nCoV group were comparable at 14 days, but numerically lower at 3 and 6 months, with GMTs of 796.4 (95% CI 635.3–998.2), 681.6 (95% CI 542.2–856.9) and 520.0 (95% CI 413.1–654.6), respectively. In contrast to pseudovirus neutralization antibodies against wild-type SARS-CoV-2, those against BA.4/5 achieved comparable levels, with the peak GMTs at 3 months of 1061.0 (95% CI 800.1–1405.5) in the IH Ad5-nCoV group and 883.0 (95% CI 670.1–1163.4) in the IM Ad5-nCoV group. Although pseudovirus neutralization antibodies against XBB.1.16 were relatively lower in both vaccine groups compared to those against wild-type and BA.4/5 SARS-CoV-2, GMTs increased significantly after booster immunization, from 79.3 at baseline to the peak of 317.0 in the IH Ad5-nCoV group, and from 65.3 at baseline to the peak of 302.8 in the IM Ad5-nCoV group, both at 3 months. Compared to participants with a history of infection, those without SARS-CoV-2 infection history had numerically lower pseudovirus neutralization antibodies against wild-type SARS-CoV-2 and BA.4/5 variant but exhibited a greater increase 14 days after booster in both vaccine groups (Fig. S6). However, no difference in pseudovirus neutralization antibodies was observed against XBB.1.16 between participants with and without SARS-CoV-2 infection history.

**Fig. 4: Pseudovirus neutralization antibodies against SARS-CoV-2 and variants in serum before and after the booster vaccination.**

Enzyme-linked immunospot (ELISpot) responses against wild-type SARS-CoV-2 were detectable before the booster dose in over 90% of participants within both vaccine groups, with a mean number of spot-forming cells per 2 × 10⁵ cells of 25.8 (95% CI 19.6–31.9) for IFN-γ and 10.2 (95% CI 7.2–13.1) for IL-2 in the IM Ad5-nCoV group, 27.8 (23.0–32.6) for IFN-γ and 6.7 (95% CI 5.1–8.6) for IL-2 in the IH Ad5-nCoV group (Fig. 5). After the booster vaccination, the levels of IFN-γ and IL-2 against wild-type SARS-CoV-2 remained comparable to baseline levels at 14 days and 3 months but showed a slight decline at 6 months. In the IH Ad5-nCoV group, the mean number of spot-forming cells per 2 × 10⁵ cells for IFN-γ was 22.3 (95% CI 13.5–31.0) at 14 days, 22.8 (95% CI 12.6–32.9) at 3 months, and 10.6 (95% CI 5.4–15.8) at 6 months, and that for IL-2 was 9.1 (95% CI 5.9–12.2) at 14 days, 7.9 (95% CI 5.8–9.9) at 3 months, and 3.7 (95% CI 0.6–6.6) at 6 months. In the IM Ad5-nCoV group, the mean number of spot-forming cells per 2 × 10⁵ cells for IFN-γ was found to be 27.3 (95% CI 15.4–39.1) at 14 days, 23.9 (95% CI 17.8–29.9) at 3 months, and 14.9 (95% CI 5.0–24.9) at 6 months, and that for IL-2 was 10.5 (95% CI 7.7–13.4) at 14 days, 8.4 (95% CI 5.9–10.8) at 3 months, and 4.3 (95% CI 1.9–6.8) at 6 months. ELISpot responses against BA.4/5 at baseline were similar to those against wild-type SARS-CoV-2 and were detectable in over 90% of participants in both vaccine groups. After the booster vaccination, no elevation in the levels of IFN-γ and IL-2 was observed as well. Besides, no difference in ELISpot responses was observed among participants with versus without SARS-CoV-2 infection history (Fig. S7).

**Fig. 5: Specific T-cell responses measured by ELISpot before and after the booster vaccination.**

The pattern of RBD-specific IgG antibody results was consistent with that of pseudovirus neutralization antibody. Specifically, the geometric mean concentration (GMC) of RBD-specific IgG antibody against wild-type SARS-CoV-2 exhibited a notable increase after vaccination in both vaccine groups, from 1071.2 (95% CI 833.1–1377.3) BAU/mL at baseline to a peak of 2174.1 (95% CI 1890.4–2500.5) BAU/mL at 14 days in the IM Ad5-nCoV group, from 1635.9 (95% CI 1339.0–1998.7) BAU/mL at baseline to a peak of 2779.8 (95% CI 2432.1–3177.2) BAU/mL at 3 months in the IH Ad5-nCoV group. In comparison, RBD-specific IgG antibody levels against BA.4/5 were notably lower, but significant increases were still observed from 14 days post-vaccination compared to baseline in both boosting groups (Fig. S3). Compared to participants with a history of infection, those without SARS-CoV-2 infection history had numerically lower baseline RBD-specific IgG antibody levels against wild-type SARS-CoV-2 and BA.4/5 variant but reached a similar or greater peak level 14 days after booster in both vaccine groups (Fig. S8).

After the booster vaccination, the geometric mean concentration (GMC) of RBD-specific IgA antibody against XBB.1.5 increased significantly in both vaccine groups, from 168.7 U/mL at baseline to the peak of 427.6 U/mL in the IM Ad5-nCoV group, and from 229.1 at baseline to the peak of 477.4 in the IH Ad5-nCoV group, at 14 days (Fig. S4). Although the GMC of RBD-specific IgA antibody against XBB.1.5 decreased slightly, it remained at a relatively high level in both vaccine groups 3 and 6 months after the booster vaccination. Similarly, the stratified results showed that participants without a SARS-CoV-2 infection history had numerically lower baseline RBD-specific IgA antibodies and reached similar peak levels 14 days after the booster compared with those with a history of infection (Fig. S9).

Safety analysis

During the six-month follow-up period after the booster vaccination, 25 episodes of serious adverse events (SAEs) were reported in 22 participants, within 9 (0.4%) of 2050 participants from the IM Ad5-nCoV group, 7 (0.3%) of 2039 participants from the IH Ad5-nCoV group, and 6 (0.3%) of 2008 participants from the control group (Table S3). The incidence of SAEs did not significantly differ between the two vaccine groups and the control group (IM Ad5-nCoV vs. control: p = 0.4618; IH Ad5-nCoV vs. control: p = 0.8025). Among the 19 SAEs reported in both vaccine groups, the most common were respiratory thoracic and mediastinal disorders (6, 31.6%) and nervous system disorders (4, 21.1%). The one with an allergic reaction in the IH Ad5-nCoV group was considered related to the vaccination, while the remaining SAEs were not vaccine-related. A comprehensive list of all SAEs is provided in Table S4.

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