Comparative immunogenicity of monovalent and bivalent adenovirus vaccines carrying spikes of early and late SARS-CoV-2 variants

The continuous emergence of highly immune-evasive SARS-CoV-2 variants has challenged vaccine efficacy. A vaccine that can provide broad protection is desirable. We evaluated the immunogenicity of a series of monovalent and bivalent adenovirus-vectored vaccines containing the spikes of Wildtype (WT), Beta, Delta, Omicron subvariants BA.1, BA.2, BA.2.12.1, BA.2.13, BA.3, BA.5, BQ.1.1, and XBB. Vaccination in mice using monovalent vaccines elicited the highest neutralizing titers against each self-matched strain, but against other variants were reduced 2− to 73-fold. A bivalent vaccine consisting of WT and BA.5 broadened the neutralizing breadth against pre-Omicron and Omicron subvariants except XBB. Among bivalent vaccines based on the strains before the emergence of XBB, a bivalent vaccine consisting of BA.2 and BA.5 elicited the most potent neutralizing antibodies against Omicron subvariants, including XBB. In mice primed with injected WT vaccine, intranasal booster with a bivalent vaccine containing XBB and BA.5 could elicit broad serum and respiratory mucosal neutralizing antibodies against all late Omicron subvariants, including XBB. In mice that had been sequentially vaccinated with WT and BA.5, intranasal booster with a monovalent XBB vaccine elicited greater serum and mucosal XBB neutralizing antibodies than bivalent vaccines containing XBB. Both monovalent and bivalent XBB vaccines induced neutralizing antibodies against EG.5. Unlike the antibody response, which is highly variant-specific, mice receiving either monovalent or bivalent vaccines elicited comparable T-cell responses against all variants. Furthermore, intranasal but not intramuscular booster induced antigen-specific lung resident T cells. This study provides insights into the design of the COVID-19 vaccine and vaccination strategies.

不断出现的高免疫逃逸型新型冠状病毒（SARS-CoV-2）变异株，对疫苗保护效力构成了严峻挑战。开发可提供广谱保护的疫苗成为迫切需求。本研究评估了一系列包含野生型（Wildtype, WT）、Beta、Delta、奥密克戎（Omicron）亚变体BA.1、BA.2、BA.2.12.1、BA.2.13、BA.3、BA.5、BQ.1.1及XBB刺突蛋白的单价及双价腺病毒载体疫苗的免疫原性。以单价疫苗免疫小鼠后，可诱导针对对应匹配毒株的最高中和效价，但针对其他变异株的中和效价会下降2至73倍。由WT与BA.5组成的双价疫苗，可拓宽针对奥密克戎流行前毒株及除XBB外的奥密克戎亚变体的中和范围。在基于XBB出现前毒株开发的双价疫苗中，由BA.2与BA.5组成的双价疫苗可诱导针对包括XBB在内的奥密克戎亚变体的最强中和抗体。在经注射式WT疫苗初免的小鼠中，使用含XBB与BA.5的双价疫苗进行鼻内加强免疫，可诱导针对包括XBB在内的所有晚期奥密克戎亚变体的广谱血清及呼吸道黏膜中和抗体。在经WT与BA.5序贯免疫的小鼠中，使用单价XBB疫苗进行鼻内加强免疫，相较于含XBB的双价疫苗，可诱导更高水平的血清及黏膜XBB中和抗体。单价及双价XBB疫苗均可诱导针对EG.5的中和抗体。与高度依赖变异株的抗体应答不同，接种单价或双价疫苗的小鼠，针对所有变异株均可诱导相当水平的T细胞应答。此外，鼻内（而非肌内）加强免疫可诱导抗原特异性肺驻留T细胞。本研究为新冠疫苗设计及免疫接种策略提供了重要参考。