A third dose of inactivated vaccine augments the potency, breadth, and duration of anamnestic responses against SARS-CoV-2

Abstract

Emergence of variants of concern (VOC) with altered antigenic structures and waning humoral immunity to SARS-CoV-2 are harbingers of a long pandemic. Administration of a third dose of an inactivated virus vaccine can boost the immune response. Here, we have dissected the immunogenic profiles of antibodies from 3-dose vaccinees, 2-dose vaccinees and convalescents. Better neutralization breadth to VOCs, expeditious recall and long-lasting humoral response bolster 3-dose vaccinees in warding off COVID-19. Analysis of 171 complex structures of SARS-CoV-2 neutralizing antibodies identified structure-activity correlates, revealing ultrapotent, VOCs-refractory and broad-spectrum antigenic patches. Construction of immunogenic and mutational heat maps revealed a direct relationship between "hot" immunogenic sites and areas with high mutation frequencies. Ongoing antibody somatic mutation, memory B cell clonal turnover and antibody composition changes in B cell repertoire driven by prolonged and repeated antigen stimulation confer development of monoclonal antibodies with enhanced neutralizing potency and breadth. Our findings rationalize the use of 3-dose immunization regimens for inactivated vaccines.

Recognition of Variants of Concern by Antibodies and T Cells Induced by a SARS-CoV-2 Inactivated Vaccine

“…Here we show using a RBD containing the mutations T478K and L452R present in the Delta variant that volunteers vaccinated with CoronaVac exhibit reduced blocking antibodies compared to the WT RBD but we report a seropositivity of 78.57% and 55.76% by sVNT and cVNT ( Tables 1 and 2 ), respectively, which suggests that the vaccine confers protection against this variant. Our data is in line with the previously mentioned works from Thailand and China in volunteers vaccinated with 2 doses of CoronaVac, in which neutralization was evaluated by cVNT and reported fold reductions of 31.7 and 3.7 fold reduction, respectively, as compared to the WT strain, whereas we report a 9.46-fold reduction ( 24 , 29 ). Similarly, mRNA vaccines induce neutralizing antibodies against the Delta variant but to a reduced extent compared to the WT strain ( 31 , 32 ).…”

“…A reduced inhibition of the interaction between hACE2 and RBD compared to the WT strain and a seropositivity of 64.2% was reported using the sVNT, the lowest across all variants of concern analyzed ( Figure 1 and Table 1 ). These results are consistent with recent reports in cohorts from Thailand and China vaccinated with CoronaVac, in which reduced neutralization was reported using live virus neutralization (fold reductions of 22.1 and 5.7 compared to the WT strain, respectively) ( 24 , 29 ) and also with the reduction in neutralizing responses observed in subjects vaccinated with the mRNA vaccine BNT162b2 for the Beta variant ( 4 , 30 ). In line with the reports for the Gamma variant, the E484K mutation found in the Beta variant has been identified as the main mutation responsible for this effect as antibodies bind to RBD with less affinity.…”

“…Our results are in line with the effectiveness of CoronaVac observed in a study of elderly subjects vaccinated in Brazil, where the Gamma variant is the most prevalent SARS-CoV-2 strain and an effectiveness of 42% was reported ( 23 ). Furthermore, our data is consistent with a recent study in volunteers vaccinated with two doses of CoronaVac in China, which exhibit a 4.3-fold reduction of VNT in live neutralization assays against the Gamma variant compared to the WT strain and another study with individuals vaccinated with two doses of CoronaVac in Brazil, which reported reduced VNT against the isolates P.1/28 and P.1/30 as compared to the WT strain (a 3.1 and 2.6 fold reduction, respectively) ( 24 , 25 ). Similarly, here we report a 4.73 fold reduction compared to the D614G strain using cVNT ( Figure 2 ).…”

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“…reported using the sVNT, the lowest across all variants of concern analyzed (Figure 1 and Table 1). These results are consistent with recent reports in cohorts from Thailand and China vaccinated with CoronaVac, in which reduced neutralization was reported using live virus neutralization (fold reductions of 22.1 and 5.7 compared to the WT strain, respectively) (24,29) and also with the reduction in neutralizing responses observed in subjects vaccinated with the mRNA vaccine BNT162b2 for the Beta variant (4,30). In line with the reports for the Gamma variant, the E484K mutation found in the Beta variant has been identified as the main mutation responsible for this effect as antibodies bind to RBD with less affinity.…”

“Overview of the Main Anti-SARS-CoV-2 Vaccines: Mechanism of Action, Efficacy and Safety” [Response To Letter]

“…Administration of a third dose of an inactivated virus vaccine (Vero cell) can boost the immune response and increase the duration of anamnestic responses against SARS-CoV-2. 7 So far the approval by the FDA of the third dose refers only to the Pfizer-BioNTech (Comirnaty®) vaccine anti-COVID-19 to allow for emergency use of a single booster dose to be administered at least six months after completion of the primary series for particular subjects. 8…”