RESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines may target epitopes that reduce durability or increase the potential for escape from vaccine-induced immunity. Using synthetic vaccinology, we have developed rationally immune-focused SARS-CoV-2 Spike-based vaccines. Glycans can be employed to alter antibody responses to infection and vaccines. Utilizing computational modeling and in vitro screening, we have incorporated glycans into the receptor-binding domain (RBD) and assessed antigenic profiles. We demonstrate that glycan-coated RBD immunogens elicit stronger neutralizing antibodies and have engineered seven multivalent configurations. Advanced DNA delivery of engineered nanoparticle vaccines rapidly elicits potent neutralizing antibodies in guinea pigs, hamsters, and multiple mouse models, including human ACE2 and human antibody repertoire transgenics. RBD nanoparticles induce high levels of cross-neutralizing antibodies against variants of concern with durable titers beyond 6 months. Single, low-dose immunization protects against a lethal SARS-CoV-2 challenge. Single-dose coronavirus vaccines via DNA-launched nanoparticles provide a platform for rapid clinical translation of potent and durable coronavirus vaccines.
Asunto(s)
Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , Nanopartículas/administración & dosificación , SARS-CoV-2/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Sitios de Unión , Vacunas contra la COVID-19/química , Vacunas contra la COVID-19/genética , Cricetinae , Epítopos , Cobayas , Inmunogenicidad Vacunal , Ratones , Nanopartículas/química , Vacunación Basada en Ácidos Nucleicos/administración & dosificación , Vacunación Basada en Ácidos Nucleicos/química , Vacunación Basada en Ácidos Nucleicos/genética , Vacunación Basada en Ácidos Nucleicos/inmunología , Polisacáridos/química , Polisacáridos/genética , Polisacáridos/inmunología , SARS-CoV-2/química , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Potencia de la VacunaRESUMEN
DNA vaccines are considered as a third-generation vaccination approach in which antigenic materials are encoded as DNA plasmids for direct in vivo production to elicit adaptive immunity. As compared to other platforms, DNA vaccination is considered to have a strong safety profile, as DNA plasmids neither replicate nor elicit vector-directed immune responses in hosts. While earlier work found the immune responses induced by DNA vaccines to be sub-optimal in larger mammals and humans, recent developments in key synthetic DNA and electroporation delivery technologies have now allowed DNA vaccines to elicit significantly more potent and consistent responses in several clinical studies. This paper will review findings from the recent clinical and preclinical studies on DNA vaccines targeting emerging infectious diseases (EID) including COVID-19 caused by the SARS-CoV-2 virus, and the technological advancements pivotal to the improved responses-including the use of the advanced delivery technology, DNA-encoded cytokine/mucosal adjuvants, and innovative concepts in immunogen design. With continuous advancement over the past three decades, the DNA approach is now poised to develop vaccines against COVID-19, as well as other EIDs.
RESUMEN
More than 100 million people have been infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Common laboratory mice are not susceptible to wild-type SARS-CoV-2 infection, challenging the development and testing of effective interventions. Here, we describe the development and testing of a mouse model for SARS-CoV-2 infection based on transduction of the respiratory tract of laboratory mice with an adeno-associated virus vector (AAV6) expressing human ACE-2 (AAV6.2FF-hACE2). We validated this model using a previously described synthetic DNA vaccine plasmid, INO-4800 (pS). Intranasal instillation of AAV6.2FF-hACE2 resulted in robust hACE2 expression in the respiratory tract. pS induced robust cellular and humoral responses. Vaccinated animals were challenged with 105 TCID50 SARS-CoV-2 (hCoV-19/Canada/ON-VIDO-01/2020) and euthanized four days post-challenge to assess viral load. One immunization resulted in 50% protection and two immunizations were completely protective. Overall, the AAV6.2FF-hACE2 mouse transduction model represents an easily accessible, genetically diverse mouse model for wild-type SARS-CoV-2 infection and preclinical evaluation of potential interventions.