A SARS DNA vaccine induces neutralizing antibody and cellular immune responses in healthy adults in a Phase I clinical trial

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 40 Convent Drive, MSC-2610, Bethesda, MD 20892-3017, USA.
Vaccine (Impact Factor: 3.62). 10/2008; 26(50):6338-43. DOI: 10.1016/j.vaccine.2008.09.026
Source: PubMed


The severe acute respiratory syndrome (SARS) virus is a member of the Coronaviridae (CoV) family that first appeared in the Guangdong Province of China in 2002 and was recognized as an emerging infectious disease in March 2003. Over 8000 cases and 900 deaths occurred during the epidemic. We report the safety and immunogenicity of a SARS DNA vaccine in a Phase I human study.
A single-plasmid DNA vaccine encoding the Spike (S) glycoprotein was evaluated in 10 healthy adults. Nine subjects completed the 3 dose vaccination schedule and were evaluated for vaccine safety and immune responses. Immune response was assessed by intracellular cytokine staining (ICS), ELISpot, ELISA, and neutralization assays.
The vaccine was well tolerated. SARS-CoV-specific antibody was detected by ELISA in 8 of 10 subjects and neutralizing antibody was detected in all subjects who received 3 doses of vaccine. SARS-CoV-specific CD4+ T-cell responses were detected in all vaccinees, and CD8+ T-cell responses in approximately 20% of individuals.
The VRC SARS DNA vaccine was well tolerated and produced cellular immune responses and neutralizing antibody in healthy adults.

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Available from: Mark K Louder, Oct 04, 2015
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    • "This system has been successfully employed in the study of highly pathogenic viruses including the influenza virus [33] and SARS-CoV [34], [35], [36]. Neutralizing antibody titers measured using pseudotyped SARS-CoV correlated well with the use of replication competent SARS-CoV [37], as such, this system has been widely used in the evaluation of SARS-CoV neutralizing antibodies [30], [38], [39], [40], [41]. In this study, the S-pps expressing human SARS-CoV S or RBD-modified chimeric S of civet SARS-CoV SZ3 strain and bat SL-CoV Rp3 and Rf1 strains were able to infect and enter CHO-ACE2 cells at similar extent (Figure S1A in File S1). "
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    ABSTRACT: The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) is the etiological agent for the infectious disease, SARS, which first emerged 10 years ago. SARS-CoV is a zoonotic virus that has crossed the species barriers to infect humans. Bats, which harbour a diverse pool of SARS-like CoVs (SL-CoVs), are believed to be the natural reservoir. The SARS-CoV surface Spike (S) protein is a major antigenic determinant in eliciting neutralizing antibody production during SARS-CoV infection. In our previous work, we showed that a panel of murine monoclonal antibodies (mAbs) that target the S2 subunit of the S protein are capable of neutralizing SARS-CoV infection in vitro (Lip KM et al, J Virol. 2006 Jan; 80(2): 941-50). In this study, we report our findings on the characterization of one of these mAbs, known as 1A9, which binds to the S protein at a novel epitope within the S2 subunit at amino acids 1111-1130. MAb 1A9 is a broadly neutralizing mAb that prevents viral entry mediated by the S proteins of human and civet SARS-CoVs as well as bat SL-CoVs. By generating mutant SARS-CoV that escapes the neutralization by mAb 1A9, the residue D1128 in S was found to be crucial for its interaction with mAb 1A9. S protein containing the substitution of D1128 with alanine (D1128A) exhibited a significant decrease in binding capability to mAb 1A9 compared to wild-type S protein. By using a pseudotyped viral entry assay, it was shown that the D1128A substitution in the escape virus allows it to overcome the viral entry blockage by mAb 1A9. In addition, the D1128A mutation was found to exert no effects on the S protein cell surface expression and incorporation into virion particles, suggesting that the escape virus retains the same viral entry property as the wild-type virus.
    PLoS ONE 07/2014; 9(7):e102415. DOI:10.1371/journal.pone.0102415 · 3.23 Impact Factor
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    • "Assessment of neutralizing activity in preclinical or clinical samples has been primarily by traditional plaque reduction neutralization (PRNT) or microneutralization (Anderson et al., 1985). PRNT suffers from limited sensitivity and nonspecificity, and is prone to technician error, is tedious, labor-intensive, and is not as reproducible as newer reporter pseudovirus methods developed for other viral diseases (Mascola et al., 2002; Pierson et al., 2006; Martin et al., 2008). Additionally the PRNT assay is time-consuming and not easily adapted to high throughput technology. "
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    ABSTRACT: Respiratory syncytial virus (RSV) is an important cause of respiratory infection in people of all ages, and is the leading cause of hospitalization in infants. Although commercially available monoclonal antibody is available for passive prophylaxis of neonates at risk of severe disease, there is no available vaccine to prevent RSV. Measurement of neutralizing activity will be a key endpoint for vaccine evaluation. Assessment of neutralizing antibody against RSV has been limited to traditional plaque reduction, which is time-consuming and inherently operator dependent and highly variable. Here, we describe a flow cytometry-based RSV-specific neutralization assay which is more rapid than traditional methods, highly sensitive and highly reproducible.
    Journal of immunological methods 10/2010; 362(1-2):180-4. DOI:10.1016/j.jim.2010.08.005 · 1.82 Impact Factor
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    • "This unformulated DNA vaccine appears to induce a similar level of immune responses to those observed in vaccinated horses protected from WNV. In addition, a recent clinical trial by these same NIH researchers tested an optimized but unformulated DNA vaccine for SARS coronavirus and demonstrated neutralizing antibodies in all subjects who received three doses of the vaccine [18]. "
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    ABSTRACT: Experiments almost 20 years ago demonstrated that injections of a sequence of DNA encoding part of a pathogen could stimulate immunity. It was soon realized that "DNA vaccination" had numerous potential advantages over conventional vaccine approaches including inherent safety and a more rapid production time. These and other attributes make DNA vaccines ideal for development against emerging pathogens. Recent advances in optimizing various aspects of DNA vaccination have accelerated this approach from concept to reality in contemporary human trials. Although not yet licensed for human use, several DNA vaccines have now been approved for animal health indications. The rapid manufacturing capabilities of DNA vaccines may be particularly important for emerging infectious diseases including the current novel H1N1 Influenza A pandemic, where pre-existing immunity is limited. Because of recent advances in DNA vaccination, this approach has the potential to be a powerful new weapon in protecting against emerging and potentially pandemic human pathogens.
    Journal of Immune Based Therapies and Vaccines 10/2009; 7(1):3. DOI:10.1186/1476-8518-7-3
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