The current threat of avian influenza to the human population, the potential for the reemergence of severe acute respiratory syndrome (SARS)-associated coronavirus, and the identification of multiple novel respiratory viruses underline the necessity for the development of therapeutic and preventive strategies to combat viral infection. Vaccine development is a key component in the prevention of widespread viral infection and in the reduction of morbidity and mortality associated with many viral infections. In this part, coronavirus vaccine, especially SARS-CoV vaccines are mainly discussed.
Coronavirus vaccines can be inactivated coronavirus, live attenuated coronavirus, or S protein-based. Besides, there are still vectored vaccines, DNA vaccines, and combination vaccines against coronaviruses. Vaccines targeting several animal CoVs have been developed, and some have been demonstrated to be efficacious in preventing viral infection. However, a phenomenon of enhanced disease following vaccination has been observed in cats upon infection with feline infectious peritonitis virus following previous infection, vaccination, or passive transfer of antibody. The phenomenon is not fully understood but is believed to be a result of enhanced uptake and spread of the virus through binding of virus-antibody immune complexes to Fc receptors on the surfaces of macrophages; low-titer (subneutralizing) antibodies directed against the S protein are mainly responsible. Although antibody enhancement appears to be limited to feline infectious peritonitis virus among CoVs, similar concerns have been raised with regard to SARS-CoV. Previously infected mice and hamsters are protected from subsequent infection with SARS-CoV in the absence of enhanced disease, and vaccine studies and passive immunoprophylaxis performed with mice and hamsters suggest that previous exposure and the presence of NAbs provide protection.
The immunogenicity and efficacy of inactivated SARS-CoV vaccines have been established in experimental animals, and one such vaccine is being evaluated in a clinical trial. However, the development of inactivated vaccines requires the propagation of high titers of infectious virus, which in the case of SARS-CoV requires biosafety level 3-enhanced precautions and is a safety concern for production. Additionally, incomplete inactivation of the vaccine virus presents a potential public health threat. Production workers are at risk for infection during handling of concentrated live SARS-CoV, incomplete virus inactivation may cause SARS outbreaks among the vaccinated populations, and some viral proteins may induce harmful immune or inflammatory responses, even causing SARS-like diseases
To date, live attenuated vaccines for SARS-CoV have not been evaluated. However, systems have been developed to generate cDNAs encoding the genomes of CoVs, including SARS-CoV. The panel of cDNAs spanning the entire CoV genome can be systematically and directionally assembled by in vitro ligation into a genome-length cDNA from which recombinant virus can be rescued. This system has been used for genetic analysis of SARS-CoV protein functions and will enable researchers to engineer specific attenuating mutations or modifications into the genome of the virus to develop live attenuated vaccines. While live attenuated vaccines targeting respiratory viruses, including influenza viruses and adenoviruses, have been approved for use in humans, the observation that infectious virus is shed in the feces of SARS-CoV-infected individuals raises concerns that a live attenuated SARS-CoV vaccine strain may also be shed in feces, with potential to spread to unvaccinated individuals. Another concern is the risk of recombination of a live attenuated vaccine virus with wild-type CoV; however, there may be ways to engineer the genome of the vaccine virus to minimize this risk.
The roles of S protein in receptor binding and membrane fusion indicate that vaccines based on the S protein could induce antibodies to block virus binding and fusion or neutralize virus infection. Among all structural proteins of SARS-CoV, S protein is the main antigenic component that is responsible for inducing host immune responses, neutralizing antibodies and/or protective immunity against virus infection. S protein has therefore been selected as an important target for vaccine and anti-viral development.
Although full-length S protein-based SARS vaccines can induce neutralizing antibody responses against SARS-CoV infection, they may also induce harmful immune responses that cause liver damage of the vaccinated animals or enhanced infection after challenge with homologous SARS-CoV, raising concerns about the safety and ultimate protective efficacy of vaccines that contain the full-length SARS-CoV S protein.
Several groups have reported preclinical evaluation of vaccines utilizing other viruses as vectors for SARS-CoV proteins, including a chimeric parainfluenza virus, MVA, rabies virus, vesicular stomatitis virus (VSV), and adenovirus. Chimeric bovine/human parainfluenza virus 3 (BHPIV3), a live attenuated parainfluenza virus vaccine candidate, was utilized as a vector for the SARS-CoV structural proteins including S, N, matrix (M), and envelope (E), alone or in combination. Studies with vectored vaccines further demonstrate that induction of S protein-specific NAbs is sufficient to confer protection.
DNA vaccines have demonstrated strong induction of immune responses to viral pathogens in animal models, specifically in mice; however, clinical data on DNA vaccines in human subjects are limited. DNA vaccines encoding the S, N, M, and E proteins of SARS-CoV have been evaluated in mice. Vaccination with S-, M-, and N-encoding DNA vaccines induced both humoral and cellular immune responses, with some variation in the relative levels of induction.
Combination vaccines have also been evaluated for their ability to augment immune responses to SARS-CoV. Administration of two doses of a DNA vaccine encoding the S protein, followed by immunization with inactivated whole virus, was shown to be more immunogenic in mice than either vaccine type alone. The combination vaccine induced both high humoral and cell-mediated immune responses. High NAb titers were also observed in mice vaccinated with a combination of S DNA vaccines and S peptide generated in Escherichia coli. Combination vaccines may enhance the efficacy of DNA vaccine candidates.
The SARS-CoV vaccine strategies reported to date demonstrate that S protein-specific NAbs alone are sufficient to provide protection against viral challenge. While SARS-CoV has not yet reemerged, its unknown reservoir leaves open the possibility that it, or a related virus, will again infect the human population. The development of vaccines targeting this virus will help, in the event of its reemergence, to potentially stop its spread before it wreaks the social and economic havoc caused by the previous outbreak. Furthermore, lessons learned from the generation of these vaccines may aid in the development of future vaccines against known and newly identified coronaviruses.
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