Immunogenicity, safety and reactogenicity of heterologous (third dose) booster vaccination with a full or fractional dose of two different COVID-19 vaccines: A phase 4, single-blind, randomized controlled trial in adults

Abstract

In this phase 4 study we assessed boosting with fractional doses of heterologous COVID-19 vaccines in Brazilian adults primed with two doses of CoronaVac (Sinovac/Butantan, São Paulo, Brazil) at least 4 months previously. Participants received either full-dose of ChAdOx1-S (Group 1, n = 232), a half dose of ChAdOx1-S (Group 2, n = 236), or a half dose of BNT162b2 (Group 3, n = 234). The primary objective was to show 80% seroresponse rates (SRR) 28 d after vaccination measured as IgG antibodies against a prototype SARS-CoV-2 spike-protein. Safety was assessed as solicited and unsolicited adverse events. At baseline all participants were seropositive, with high IgG titers overall. SRR at Day 28 were 34.3%, 27.1% and 71.2%, respectively, not meeting the primary objective of 80%, despite robust immune responses in all three groups with geometric mean-fold rise (GMFR) in IgG titers of 3.39, 2.99 and 7.42, respectively. IgG immune responses with similar GMFR were also observed against SARS-CoV-2 variants, Alpha, Beta, Delta, Gamma and D614G. In subsets (n = 35) of participants GMFR of neutralizing immune responses against live prototype SARS-CoV-2 virus and Omicron BA.2 were similar to the IgG responses as were pseudo-neutralizing responses against SARS-CoV-2 prototype and Omicron BA.4/5 variants. All vaccinations were well tolerated with no vaccine-related serious adverse events and mainly transient mild-to-moderate local and systemic reactogenicity. Heterologous boosting with full or half doses of ChAdOx1-S or a half dose of BNT162b2 was safe and immunogenic in CoronaVac-primed adults, but seroresponse rates were limited by high baseline immunity.

Keywords: BNT162b2; COVID-19; ChAdOx1-S; fractional dose; heterologous booster; neutralizing antibodies; vaccine.

Figure 1.

Study flow chart.

Figure 2.

Incidences rates of participants reporting solicited local and systemic adverse events by highest severity, in days 0–7 after vaccination in the three study groups. One case of moderate swelling in the half-dose ChAdOx1 group is not shown.

Figure 3.

Geometric mean concentrations (95% CI) of anti-prototype spike IgG antibodies in the three study groups before and after vaccination. Values above columns show geometric mean-fold rises (GMFR, with 95% CI) from Day 0 to Day 28. Panel a shows all samples per group, Panel B shows segregation according to self-reported history of prior COVID-19 infection at baseline.

Figure 4.

Anti-spike IgG concentrations in the three study groups at Day 0 and 28, with lines between the two samples for each individual participant. Box plots represent median and 25th and 75th percentiles.

Figure 5.

Geometric mean concentrations (95% CI) of anti-spike IgG antibodies for the indicated SARS-CoV-2 variants in the three study groups before and after vaccination. Values above columns show geometric mean-fold rises (GMFR) with 95% CI) from Day 0 to Day 28.