SARS vaccines: where are we?

Rachel L. Roper; Kristina E. Rehm

Disclosures

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

In This Article

Abstract and Introduction

Abstract

In this review, the current state of vaccine development against human severe acute respiratory syndrome (SARS) coronavirus, focusing on recently published data is assessed. We discuss which strategies have been assessed immunologically and which have been evaluated in SARS coronavirus challenge models. We discuss inactivated vaccines, virally and bacterially vectored vaccines, recombinant protein and DNA vaccines, as well as the use of attenuated vaccines. Data regarding the correlates of protection, animal models and the available evidence regarding potential vaccine enhancement of SARS disease are discussed. While there is much evidence that various vaccine strategies against SARS are safe and immunogenic, vaccinated animals still display significant disease upon challenge. Current data suggest that intranasal vaccination may be crucial and that new or combination strategies may be required for good protective efficacy against SARS in humans.

Introduction

Severe acute respiratory syndrome (SARS) caused 8098 reported human infections and 774 deaths in 32 countries in a single fall-to-spring period (2002-2003), and also led to travel restrictions and significant effects on the global economy.[201] The etiologic agent of SARS was identified as a new human coronavirus (CoV), order Nidovirales, family Coronaviridae, by the sequencing of its genome[1,2] and by experimental infection of macaques to fulfill Koch's postulates.[3] Serologic evidence suggests zoonotic transmission of SARS-associated CoV (SARS-CoV) into the human population for several years before the recognized outbreak,[4] and transmission to humans has continued, resulting in at least four independent nonlaboratory-associated cases in 2004.[5,6,7,202] The movement of SARS-CoV into the human population over several years suggests a need to prepare vaccines for protection from this potentially emerging agent. SARS-CoV is of particular concern as a zoonosis because it can replicate in a large number of animals including dogs, cats, pigs, mice, ferrets, foxes, monkeys and rats,[8,9,10] in addition to Chinese palm civets, raccoon-dogs and bats, which appear to be the natural host.[11,12]

SARS is primarily a respiratory disease, with the highest concentration of SARS-CoV found in the respiratory tract,[13,14,15] although this virus is also detectable in other organs and tissues, as well as in stool.[16,17,18] The incubation period for the disease ranges from 2 to 10 days, and infectivity is maximal during the second week of disease.[19,20] The disease is characterized by fever, chills, malaise, dyspnea, cough, diarrhea and pneumonia.[13,14,15] Diffuse alveolar damage along with inflammatory cell infiltrate consisting particularly of macrophages are hallmarks found in SARS patients.[21] The fever of most patients abates within 2 weeks and is accompanied by resolution of chest symptoms and radiologic changes.[3,13,14,15,22] The major mode of transmission of SARS-CoV is believed to be through droplet spread,[2,23] although SARS-CoV can remain viable when dried on surfaces for up to 6 days.[24] The majority of SARS patients are adults with only a few cases in children aged 15 years or younger.[19,20,25] The overall case-fatality rate is approximately 10%.[19,203]

Currently, there are no approved antiviral drugs that effectively target SARS-CoV, hence vaccination is the most likely mode of preventing SARS in people, especially for those at highest risk (e.g., healthcare workers). A successful SARS vaccine could be used prophylactically to protect healthcare workers, laboratory personnel and other at-risk individuals. No vaccines are currently licensed for any of the human CoVs, but vaccines have been produced for a number of CoVs for use in chickens, cattle, dogs, cats and swine.[26,27,28]

The positive-stranded RNA genome of SARS-CoV is 29.7 kb in length and contains approximately 14 open reading frames (ORFs), described in Table 1 , with identification of each ORF by the four nomenclature systems.[1,2] These ORFs encode proteins that provide targets for vaccine and drug development. CoV enters target cells via receptor-mediated endocytosis driven by the spike (S) glycoprotein, which protrudes from the surface of the virion. The S protein serves as the major viral attachment protein, critical to virus binding and fusion of the viral envelope,[29] and thus has been a major target antigen for vaccine development. The receptor-S protein interaction is a major determinant of species specificity and tissue tropism for CoV.[30] Angiotensin-converting enzyme 2 (ACE2) and CD209L were identified as functional receptors for SARS-CoV; however, entry through ACE2 is more efficient.[31,32] The receptor-binding domain of the S protein is a critical neutralization determinant.

Several strategies may be considered for vaccination against SARS-CoV, including an inactivated or whole-killed virus (WKV) vaccine, a live-attenuated SARS-CoV vaccine, a viral vector such as adenovirus (Ad) or vaccinia virus expressing SARS-CoV genes, bacterial vectors, recombinant SARS-CoV proteins or DNA vaccines. Live-attenuated CoV, killed CoV, DNA vaccines and viral vectored vaccines have all been used to successfully vaccinate against animal CoVs.[28,33,34]

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