SARS vaccines: where are we?

Rachel L. Roper; Kristina E. Rehm

Disclosures

Expert Rev Vaccines. 2009;8(7):887-898. 

In This Article

Recombinant Vector Vaccines

Recombinant virus vaccines have several features that make them efficient in inducing B- and T-cell-mediated immune responses, including their ability to infect cells and persist in the body, their ability to infect antigen-presenting cells directly, and the fact that viral proteins and the infection itself can have strong adjuvant activity.[56] Recombinant viruses express the foreign target protein in the cytoplasm of the host cell, much like an intracellular pathogen. Thus, the endogenous antigen is available for processing by the cellular antigen-processing machinery for expression with MHC class I for presentation to CD8+ T lymphocytes and development of cytotoxic T cells. As a result, recombinant viruses result in activation of cellular immunity often necessary for elimination of infected cells. For SARS-CoV vaccines, several viruses have been used to express SARS-CoV proteins with the goal of inducing both strong cellular immunity and neutralizing antibodies.

Adenovirus Vectored SARS-CoV Vaccines

Some of the advantages of Ad vaccines include their lack of pathogenicity in humans, especially for replication-deficient mutants,[57] oral or nasal administration, which promotes mucosal immunity, and the well-characterized genome of Ads.[58] Disadvantages of Ads compared with other viral delivery systems include their limited cloning capacity, the fact that human Ads have a restricted host range, often making animal testing difficult,[59] and that a large percentage of the human population has pre-existing immunity against the vector due to natural infections.[56] The last difficulty may be circumvented by the use of prime-boost protocols where a different vector (e.g., DNA vaccine) is used to prime the immune response followed by a boost with a recombinant Ad.[56]

First, it was demonstrated that Ad vectors encoding SARS proteins were immunogenic. Rhesus macaques immunized intramuscularly with a combination of three Ad5-SARS-CoV Ad-based vectors (N, S and M protein) all generated antibody responses against spike S1 fragment, SARS-CoV-neutralizing antibodies and T-cell responses against the N protein.[60] Vaccination of C57BL/6 mice with recombinant SARS N protein-Ad was able to induce SARS-CoV-specific IFN-γ secretion and T-cell proliferation, but not neutralizing antibodies.[57]

Protection against SARS-CoV challenge by Ad-vectored vaccines was first tested in mice.[49] We developed recombinant Ad constructs expressing genes for either SARS-CoV S or N proteins, and immunized SARS-CoV-susceptible 129S6/SvEv mice[61] with both vectors combined, either intranasally or intramuscularly. The vaccine induced high levels of neutralizing antibody, anti-SARS-CoV N protein IFN-γ secretion, and significantly reduced viral titers and RNA in the lungs of challenged mice.[49] Interestingly, although the intramuscular route was more effective in inducing neutralizing SARS serum antibodies, the intranasal route of administration induced IgA and was more effective in blocking SARS-CoV replication in nose and lung tissue (1000-fold in nasal secretions). This finding suggests that the intranasal administration of recombinant Ad N and S proteins may induce crucial protective mucosal immunity. In the same study, we compared adeno-vectored S and N vaccines with a preparation of inactivated SARS-CoV. The combined adeno-S and -N vaccine induced significantly lower neutralizing antibodies and similar anti-N IFN-γ-secreting cells compared with inactivated SARS-CoV vaccine, but the inactivated vaccine provided superior protection measured as SARS-CoV lung titers and RNA.[49] We also compared these vaccines in a ferret model in which ferrets show clinical signs, including fever and lung damage.[52] Both the whole-killed SARS-CoV vaccine and the combination of Ads encoding N and S proteins induced neutralizing antibody responses, reduced viral replication in the respiratory tract, and decreased tissue damage in the thymus and lungs.[52] The adeno-S and -N vaccine delivered intranasally elicited a poor serum-neutralizing antibody response but provided the best protection from lung replication and lung damage,[52] indicating that serum-neutralizing antibodies are not a sufficient measure of protective efficacy of a vaccine. In addition, despite high neutralizing antibody titers in some vaccines, protection was incomplete for all vaccine preparations (with one homologous boost) and administration routes, suggesting that combinations of vaccines may be necessary to provide adequate protection against SARS in susceptible animals and humans.

Adenovirus constructs expressing SARS-CoV S protein have also been evaluated in a ferret model using a heterologous prime-boost with human and chimpanzee Ads in order to avoid interference from the immune response to the first Ad vaccination during the boost. This vaccine regimen reduced viral load and the severity of pneumonia in ferrets, and it was also shown to be immunogenic in rhesus macaques.[51]

Poxvirus Vectors

Poxvirus recombinants are attractive as vaccine vectors owing to their ease of production, stability, capacity for encoding large genes, cytoplasmic gene expression, and ability to induce long-lasting cellular and humoral immune responses.[56] The replication-deficient poxvirus vector, modified vaccinia Ankara (MVA) strain, encoding SARS-CoV S protein delivered either intranasally or intramuscularly, induced neutralizing antibodies and reduced viral replication in the respiratory tract of challenged mice.[62] An MVA-S recombinant vaccine was also employed in one ferret study with apparent increased liver pathology in vaccinated groups after SARS-CoV challenge.[63] While these data suggest that liver pathology be evaluated in SARS-CoV vaccine studies, no other report has shown liver damage linked to vaccination.[62]

Recombinant Platform Vaccines

Several other viral and bacterial vaccine platform technologies have been employed to encode S protein for SARS-CoV vaccine development. Monkeys vaccinated intranasally with parainfluenza encoding the SARS-CoV S protein produced neutralizing antibodies and had significantly reduced viral titers in the respiratory tract after challenge.[64] Parainfluenza virus encoding the S protein was also protective from SARS-CoV challenge in hamsters, and the inclusion of M and E proteins enhanced efficacy.[65] Recombinant adeno-associated virus encoding SARS-CoV S protein vaccine induced SARS-CoV neutralizing antibodies, T-cell responses, and decreased viral titers and lung damage in mice.[66] As with the Ad studies,[49,52] intranasal administration led to IgA production and improved protection from SARS-CoV challenge. Newcastle disease virus, an avian-tropic virus that exhibits limited replication in primate respiratory tissues, was also used for SARS-CoV vaccination. Monkeys vaccinated with Newcastle disease virus expressing S protein had up to 1000-fold less virus in the lung tissue after SARS-CoV challenge.[67] A replication-defective vesicular stomatitis virus recombinant expressing the SARS-CoV S protein induced neutralizing antibodies and T-cell responses, and provided protection of immunized mice from SARS-CoV.[68]

Several other recombinant strategies have been tested for immunogenicity but not yet for efficacy. For example, live-attenuated recombinant measles viruses expressing SARS-CoV S and N proteins both induced high antibody titers against their cognate antigen. Anti-S antibodies were SARS-CoV neutralizing and N protein induced specific cellular immune responses.[69] Rabies vector has been used to express S proteins and elicit neutralizing antibodies in mice.[70] Recombinant baculoviruses expressing N or S proteins induced both humoral and cellular immune responses in vaccinated mice.[71] Attenuated Salmonella expressing SARS-CoV N protein elicited cytotoxic T-lymphocyte activities and induced IFN-γ-producing T cells in mice. Interestingly, intranasal vaccination also showed advantages in this bacterial system, inducing the highest IgG and IgA levels.[72]

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