Mucosal immunisation and immunoprophylaxis as potential strategies for prevention of SARS
Authors: AR Foxwell, AW Cripps
Journal: The Lancet (2004)

Severe acute respiratory syndrome (SARS) is a rapid-onset atypical pneumonia that was first identified in epidemic proportions in China in 2002.1World Health OrganizationSummary table of SARS cases by country, 1 November 2002–7 August 2003. Aug 15, 2003.http://www.who.int/csr/sars/country/2003_08_15/en/Google Scholar WHO recently announced the containment of the latest outbreak, which was centred on the National Institute of Virology in Beijing.2China's latest SARS outbreak has been contained, but biosafety concerns remain-Update 7. May 18, 2004.http://www.who.int/csr/don/2004_05_18a/en/Google Scholar In today's Lancet, Alexander Bukreyev and colleagues show that a single intranasal immunisation in African green monkeys with the attenuated bovine/human parainfluenza virus type 3 (BHPIV3), into which the envelope spike (S) protein from the SARS coronavirus (SARS-CoV) has been expressed, induced neutralising antibodies to SARS-CoV in serum, and protected against subsequent live-viral challenge with SARS-CoV. This finding is important since it brings together known yet innovative technologies, knowledge, and skills to address prevention of an emerging infectious disease. If applicable generally, the result could represent a major step forward for simplifying mass immunisation in at-risk human populations. On the basis that the S protein of other coronaviruses induced virus-specific immunity and, in some cases, protection against subsequent challenge in animal models,3Daniel C Talbot PJ Protection from lethal coronavirus infection by affinity-purified spike glycoprotein of murine hepatitis virus, strain A59.Virology. 1990; 174: 87-94Crossref PubMed Scopus (32) Google Scholar Bukreyev and colleagues used a well-documented carrier vector, BHPIV,3Daniel C Talbot PJ Protection from lethal coronavirus infection by affinity-purified spike glycoprotein of murine hepatitis virus, strain A59.Virology. 1990; 174: 87-94Crossref PubMed Scopus (32) Google Scholar, 4Schmidt AC McAuliffe JM Huang A et al.Bovine parainfluenza virus type 3 (BPIV3) fusion and hemagglutinin-neuraminidase glycoproteins make an important contribution to the restricted replication of BPIV3 in primates.J Virol. 2000; 74: 8922-8929Crossref PubMed Scopus (78) Google Scholar to create a live-attenuated vaccine that protects monkeys against challenge with SARS-CoV. Several animal viruses display the type of stable host-range restriction that led to the development of the Jennerian approach to live-attenuated vaccines, as used in creating the BHPIV3 vector. This chimeric vector has important potential in inducing protective immune responses against respiratory syncytial virus (A and B) and human parainfluenza virus (type 3) in rhesus monkeys and hamsters.5Schmidt AC McAuliffe JM Murphy BR Collins PL Recombinant bovine/human parainfluenza virus type 3 (B/HPIV3) expressing the respiratory syncytial virus (RSV) G and F proteins can be used to achieve simultaneous mucosal immunization against RSV and HPIV3.J Virol. 2001; 75: 4594-4603Crossref PubMed Scopus (89) Google Scholar, 6Schmidt AC Wenzke DR McAuliffe JM et al.Mucosal immunization of rhesus monkeys against respiratory syncytial virus subgroups A and B and human parainfluenza virus type 3 by using a live cDNA-derived vaccine based on a host range-attenuated bovine parainfluenza virus type 3 vector backbone.JVirol. 2002; 76: 1089-1099Crossref PubMed Scopus (74) Google Scholar Human trials show that the live-attenuated bovine parainfluenza virus type 3 (BPIV3) is safe, immunogenic, and stable in infants and children,7Karron RA Wright PF Hall SL et al.A live attenuated bovine parainfluenza virus type 3 vaccine is safe, infectious, immunogenic, and phenotypically stable in infants and children.J InfectDis. 1995; 171: 1107-1114Crossref Scopus (115) Google Scholar and BHPIV3 produces enhanced immunogenicity against disease in rhesus monkeys.6Schmidt AC Wenzke DR McAuliffe JM et al.Mucosal immunization of rhesus monkeys against respiratory syncytial virus subgroups A and B and human parainfluenza virus type 3 by using a live cDNA-derived vaccine based on a host range-attenuated bovine parainfluenza virus type 3 vector backbone.JVirol. 2002; 76: 1089-1099Crossref PubMed Scopus (74) Google Scholar Data are not yet available on the use of the BHPIV3 chimeric vector in human trials. Intranasal live-attenuated viral vectors offer the best possibility of inducing sustainable protective immunity via the mucosal route. In the host-restricted approach to attenuation, it has been seen that: powerful adjuvants are not required;6Schmidt AC Wenzke DR McAuliffe JM et al.Mucosal immunization of rhesus monkeys against respiratory syncytial virus subgroups A and B and human parainfluenza virus type 3 by using a live cDNA-derived vaccine based on a host range-attenuated bovine parainfluenza virus type 3 vector backbone.JVirol. 2002; 76: 1089-1099Crossref PubMed Scopus (74) Google Scholar that both systemic and mucosal immune responses are generated;7Karron RA Wright PF Hall SL et al.A live attenuated bovine parainfluenza virus type 3 vaccine is safe, infectious, immunogenic, and phenotypically stable in infants and children.J InfectDis. 1995; 171: 1107-1114Crossref Scopus (115) Google Scholar and that exacerbation of disease after natural exposure does not seem to occur.8Kim HW Canchola JG Brandt CD et al.Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine.Am J Epidemiol. 1969; 89: 422-434Crossref PubMed Scopus (1541) Google Scholar Additionally, mucosal immunisation offers the advantage that mucosal immune mechanisms seem to mature earlier in young children and wane later in elderly people than with systemic immune mechanisms.9Cripps AW Gleeson M Ontogeny of mucosal immunity and aging.in: Ogra PL Mestecky J Lamm ME Stroler W Brenenstock J McGhee JR Mucosal immunology. 2nd edn. Academic Press, San Diego1999: 253-266Google Scholar Despite the promise demonstrated by the Jennerian approach and in particular the BHPIV3/SARS-S intranasal vaccine, we need to know the lag before both mucosal and systemic immune mechanisms are effective, and also the duration of immunity induced. Bukreyev and colleagues only report challenging the monkeys with SARS-CoV at 28 days after immunisation. Whilst the immunisation gave excellent protection from viral shedding at 28 days, the serum concentration of antibody in immunised animals was not greater at 28 days post-challenge than that measured in non-immunised animals. Further studies examining which mucosal immune responses are induced to SARS-CoV and which of these have any role in immune protection need to be done. Dose-response studies for both immunisation and challenge will also be needed before this model can be adopted for human trials. As indicated by Bukreyev and colleagues, the approach they used of a replicating chimeric viral vector with protein inserts from a common human respiratory pathogen might be limited to infants and small children, because of interference from neutralising antibodies developed through natural infection.10Clements ML Belshe RB King J et al.Evaluation of bovine, cold-adapted human, and wild-type human parainfluenza type 3 viruses in adult volunteers and in chimpanzees.JClin Microbiol. 1991; 6: 1175-1182Google Scholar Further investigations are warranted to establish a vector construct that would be effective in all age groups, especially because of the increased mortality rate from SARS in elderly people.11Donnelly CA Ghani AC Leung GM et al.Epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong.Lancet. 2003; 361: 1761-1766Summary Full Text Full Text PDF PubMed Scopus (786) Google Scholar Possibilities for immuoprophylaxis and treatment of high-risk individuals who have become exposed to SARS-CoV are outlined in a Research letter, also in today's Lancet, by Jan ter Meulen and colleagues. These researchers describe preliminary experiments in the ferret, a species that can be naturally infected with SARS-CoV. They found that prophylactic treatment of infected animals with a human monoclonal antibody (directed against the cell-surface spike glycoprotein of SARS-CoV) abrogated viral shedding from the pharynx, and prevented the development of macroscopic lung disease in infected animals. Extrapolation to human beings of a prophylactic treatment that reduced viral shedding and lung lesions would probably reduce transmission and the high morbidity associated with the disease. Such a strategy, in combination with immunisation during a SARS outbreak, would offer potential treatment and prophylactic applications. However, before the monoclonal antibody approach suggested by ter Meulen can be applied to human beings, several further studies are required. Of particular importance are experiments relating to the efficacy of immunoprophylaxis and treatment in the presence of an established infection, appropriate dose-response and safety studies, and, critically, study of the effect of circulating antibody on vaccine efficacy.12Crowe Jr, JE Firestone CY Murphy BR Passively acquired antibodies suppress humoral but not cell-mediated immunity in mice immunized with live attenuated respiratory syncytial virus vaccines.J Immunol. 2001; 167: 3910-3918Crossref PubMed Scopus (94) Google Scholar Bukreyev, ter Meulen, and their colleagues have shown that SARS can be effectively prevented by immunisation of the mucosa of the respiratory tract and immunoprophylaxis in animal models. Whilst further studies are required before these concepts can be applied to human beings, the findings provide exciting strategies for the prevention of disease in target communities and treatment of at-risk individuals. We have no conflict of interest to declare. Mucosal immunisation of African green monkeys (Cercopithecus aethiops) with an attenuated parainfluenza virus expressing the SARS coronavirus spike protein for the prevention of SARSA vectored mucosal vaccine expressing the SARS-coronavirus S protein alone may be highly effective in a single-dose format for the prevention of SARS. Full-Text PDF Human monoclonal antibody as prophylaxis for SARS coronavirus infection in ferretsSARS coronavirus continues to cause sporadic cases of severe acute respiratory syndrome (SARS) in China. No active or passive immunoprophylaxis for disease induced by SARS coronavirus is available. We investigated prophylaxis of SARS coronavirus infection with a neutralising human monoclonal antibody in ferrets, which can be readily infected with the virus. Prophylactic administration of the monoclonal antibody at 10 mg/kg reduced replication of SARS coronavirus in the lungs of infected ferrets by 3·3 logs (95% Cl 2·6–4·0 logs; p<0·001), completely prevented the development of SARS coronavirus-induced macroscopic lung pathology (p=0·013), and abolished shedding of virus in pharyngeal secretions. Full-Text PDF