The Bivalent COVID-19 Booster Immunization after Three Doses of Inactivated Vaccine Augments the Neutralizing Antibody Response against Circulating Omicron Sublineages.

A fourth dose of a COVID-19 vaccine has been recommended by a number of authorities due to waning immunity over time and the emergence of immune-escaping variants. Here, we evaluated the safety and immunogenicity of the bivalent BV-01-B5 or V-01D-351 or the prototype V-01 for heterologous boosting in three-dose inactivated COVID-19 vaccine (ICV) recipients, in comparison with ICV homologous boosting. One pilot study (NCT05583357) included 20 participants randomized at 1:1, either receiving V-01D-351 or CoronaVac. The other one (NCT05585567) recruited 36 participants randomized at 2:1, either receiving BV-01-B5 or V-01, respectively. BV-01-B5, V-01D-351, and V-01 were safe and well-tolerated as heterologous booster shots after three doses of ICV, with adverse reactions predominantly being mild and moderate in severity, similar to the safety profile of ICV boosters. The bivalent V-01D-351 and BV-01-B5 and prototype V-01 booster demonstrated remarkable cross-reactive immunogenicity against the prototype and multiple emerging variants of concern (VOCs), with the geometric mean ratio (versus CoronaVac) in particular being 31.3 (500 vs. 16), 12.0 (192 vs. 16) and 8.5 (136 vs.16) against BA.4/5 14 days after the booster, respectively. Taken together, the modified bivalent-formulation V-01 boosters induced robust neutralizing responses against multiple Omicron sublineages, better than V-01 and remarkably superior to ICV booster, without compromising the safety and tolerability.

A Heterologous V-01 or Variant-Matched Bivalent V-01D-351 Booster following Primary Series of Inactivated Vaccine Enhances the Neutralizing Capacity against SARS-CoV-2 Delta and Omicron Strains.

Immune escape of emerging SARS-CoV-2 variants of concern (VOCs) and waning immunity over time following the primary series suggest the importance and necessity of booster shot of COVID-19 vaccines. With the aim to preliminarily evaluate the potential of heterologous boosting, we conducted two pilot studies to evaluate the safety and immunogenicity of the V-01 or a bivalent V-01D-351 (targeting Delta and Beta strain) booster after 5-7 months of the primary series of inactivated COVID-9 vaccine (ICV). A total of 77 participants were enrolled, with 20 participants in the V-01D-351 booster study, and 27, 30 participants in the age stratified participants of V-01 booster study. The safety results showed that V-01 or V-01D-351 was safe and well-tolerated as a heterologous booster shot, with overall adverse reactions predominantly being absent or mild in severity. The immunogenicity results showed that the heterologous prime-boost immunization with V-01 or bivalent V-01D-351 booster induced stronger humoral immune response as compared with the homologous booster with ICV. In particular, V-01D-351 booster showed the highest pseudovirus neutralizing antibody titers against prototype SARS-CoV-2, Delta and Omicron BA.1 strains at day 14 post boosting, with GMTs 22.7, 18.3, 14.3 times higher than ICV booster, 6.2, 6.1, 3.8 times higher than V-01 booster (10 µg), and 5.2, 3.8, 3.5 times higher than V-01 booster (25 µg), respectively. The heterologous V-01 booster also achieved a favorable safety and immunogenicity profile in older participants. Our study has provided evidence for a flexible roll-out of heterologous boosters and referential approaches for variant-specific vaccine boosters, with rationally conserved but diversified epitopes relative to primary series, to build herd immunity against the ongoing pandemic.

Sequential immunization with SARS-CoV-2 RBD vaccine induces potent and broad neutralization against variants in mice.

The current COVID-19 pandemic caused by constantly emerging SARS-CoV-2 variants still poses a threat to public health worldwide. Effective next-generation vaccines and optimized booster vaccination strategies are urgently needed. Here, we sequentially immunized mice with a SARS-CoV-2 wild-type inactivated vaccine and a heterologous mutant RBD vaccine, and then evaluated their neutralizing antibody responses against variants including Beta, Delta, Alpha, Iota, Kappa, and A.23.1. These data showed that a third booster dose of heterologous RBD vaccine especially after two doses of inactivated vaccines significantly enhanced the GMTs of nAbs against all SARS-CoV-2 variants we tested. In addition, the WT and variants all displayed good cross-immunogenicity and might be applied in the design of booster vaccines to induce broadly neutralizing antibodies.

Interferon-armed RBD dimer enhances the immunogenicity of RBD for sterilizing immunity against SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global crisis, urgently necessitating the development of safe, efficacious, convenient-to-store, and low-cost vaccine options. A major challenge is that the receptor-binding domain (RBD)-only vaccine fails to trigger long-lasting protective immunity if used alone for vaccination. To enhance antigen processing and cross-presentation in draining lymph nodes (DLNs), we developed an interferon (IFN)-armed RBD dimerized by an immunoglobulin fragment (I-R-F). I-R-F efficiently directs immunity against RBD to DLNs. A low dose of I-R-F induces not only high titers of long-lasting neutralizing antibodies (NAbs) but also more comprehensive T cell responses than RBD. Notably, I-R-F provides comprehensive protection in the form of a one-dose vaccine without an adjuvant. Our study shows that the pan-epitope modified human I-R-F (I-P-R-F) vaccine provides rapid and complete protection throughout the upper and lower respiratory tracts against a high-dose SARS-CoV-2 challenge in rhesus macaques. Based on these promising results, we have initiated a randomized, placebo-controlled, phase I/II trial of the human I-P-R-F vaccine (V-01) in 180 healthy adults, and the vaccine appears safe and elicits strong antiviral immune responses. Due to its potency and safety, this engineered vaccine may become a next-generation vaccine candidate in the global effort to overcome COVID-19.