Fractionating a COVID-19 Ad5-vectored vaccine improves virus-specific immunity

Abstract

SARS-CoV-2 has caused a global pandemic that has infected more than 230 million people worldwide. Although several vaccine candidates have received emergency use authorization (EUA), there is still limited knowledge on how vaccine dosing affects immune responses. We performed mechanistic studies in mice to understand how the priming dose of an adenovirus-based SARS-CoV-2 vaccine affects long-term immunity to SARS-CoV-2. We first primed C57BL/6 mice with an adenovirus serotype 5 vaccine encoding the SARS-CoV-2 spike protein, similar to that used in the CanSino and Sputnik V vaccines. The vaccine prime was administered either at a standard dose or 1000-fold lower dose, followed by a boost with the standard dose four weeks later. Initially, the low dose prime induced lower immune responses relative to the standard dose prime. However, the low dose prime elicited immune responses that were qualitatively superior, and upon boosting, exhibited significantly more potent recall and functional capacity. We also report similar effects with a simian immunodeficiency virus (SIV) vaccine. These findings show an unexpected advantage of fractionating vaccine prime doses, warranting a re-evaluation of vaccine trial protocols for SARS-CoV-2 and other pathogens.

Status of Humoral and Cellular Immune Responses within 12 Months following CoronaVac Vaccination against COVID-19

“…Moreover, a prominent population of CD4 + and CD8 + memory T cells were biased toward T CM , T EM , and T E subsets through 12 months post-booster vaccination. Research has shown that T EM and T E subsets exhibit rapid cytotoxicity to eliminate the infected cells but tend to be more short-lived than T CM ( 22 ). Conversely, the T CM subset exhibits superior recall capacity ( 22 ).…”

“…Research has shown that T EM and T E subsets exhibit rapid cytotoxicity to eliminate the infected cells but tend to be more short-lived than T CM ( 22 ). Conversely, the T CM subset exhibits superior recall capacity ( 22 ). Although the classical immunological theory suggests that the inactivated vaccines are not thought to induce CD8 + T-cell responses, our data suggest that the structural integrity of whole SARS-CoV-2 might be the key to elicit antiviral CD8 + memory T-cell responses ( 23 ).…”

Nucleocapsid-specific humoral responses improve the control of SARS-CoV-2

“…As positive control, we used sera from mice that received a spike-based adenovirus vaccine (Ad5-S, similar to the CanSino vaccine and the Sputnik vaccine). As expected (Dangi et al ., 2021b; Sanchez et al, 2021), sera from mice that received this spike-based vaccine prevented SARS-CoV-2 infection, even when the sera were diluted 450-fold ( Figure 2B ). However, sera from mice that received the nucleocapsid-based vaccine did not exert any antiviral effect in this in vitro infection assay ( Figure 2B–2C ).…”

Fighting Fire with Fire: Immunogenicity of Viral Vectored Vaccines against COVID-19

“…In BALB/c mice, a single mucosal immunization of Ad5 encoding the full-length S protein (Ad5-nCoV) induced robust binding and neutralizing antibody responses and protected the lungs of mice from SARS-CoV-2 infection [22]. In C57BL/6 mice, a low-dose prime (LD, 1 × 10 6 vp) with a standard dose boost (SD, 1 × 10 9 vp) of an Ad5-based vaccine encoding S led to a 72-fold increase in NAbs and superior CD8+ T cell responses compared with the SD/SD regimen [23]. Indeed, this observation aligns with a recent ChAdOx1 nCoV-19 (AZD1222) clinical trial, in which a half-dose prime conferred greater protective efficacy than a standard-dose prime [24].…”

“…Therefore, there may exist a threshold for the induction of optimal protection, above which vaccinating with higher doses leads to immune exhaustion, and below which vaccinating with lower doses fails to generate sufficient immunity against pathogens. Further, Sanchez et al mechanistically found that lowering the priming dose generated higher central memory CD8+ T cells and fewer exhausted T cells, which underpin dose-sparing as a strategy to improve recall response and vaccine accessibility [23]. In CD-1 mice, a prime-boost immunization of a dual antigen vaccine expressing modified SARS-CoV-2 S and nucleocapsid (N) proteins (hAd5 S-Fusion + N-ETSD) by the subcutaneous route (SC) elicited stronger anti-S IgG2a, IgG2b, and NAb responses compared with hAd5 S-WT; the researchers ascribed the improvement in antibody response to enhanced cell surface expression of S-Fusion [25].…”