Virology tidbits

Virology tidbits

Thursday, 18 September 2014

MERS-CoV vaccine

MERS-CoV is the causative agent of a severe and fatal respiratory illness in humans with no known effective antiviral therapy or vaccine. Although MERS-CoV infections have been reported from countries outside the Arabian peninsula, local transmission with the exception of family cluster of three cases in Tunisia (with the index case being infected in the KSA) has been limited to the Kingdom of Saudi Arabia, the Kingdom of Jordan, Qatar, Oman, and the United Arab Emirates. Both antibodies binding to the S (spike) protein of MERS-CoV and virus neutralising antibodies have been detected in dromedary camels and linked to two confirmed human cases in Qatar and the sequence of  an isolate from a Qatari dromedary camel is highly similar to an isolate obtained from a patient in the UK, England/Qatar1. Dromedary camel to human transmission has also been reported from a case in the KSA, and antibodies against a MERS-CoV like virus have been detected retrospectively in samples from camels in Kenya dating back as far as 1992, suggesting that camels and/or dromedary camels might either be a natural reservoir or at least involved in the transmission of MERS-CoV. Also, viral strains isolated from dromedary camels in the KSA and Egypt (Dromedary/Al-Hasa-KFU-HKU13/2013, Dromedary/Al-Hasa-KFU-HKU19D/2013,Dromedary/Egypt-NRCE-HKU270/2013) are able to infect VeroE6 and human Calu-3  (human respiratory tract) cells with similar kinetics.
Regarding the origin of MERS-CoV, recent data showed that a MERS-CoV related betacoronavirus has been isolated from Vespertilio superans bats in China and sequence analysis of the South African Neoromicia capensis bat CoV (Neo-CoV) suggests that Neo-CoV might be an ancestor of MERS-CoV. Indeed, it has been suggested that bats -or to be precise fecal matter of bats- transmit CoV to a variety of species including but not limited to  human, horses, camels, and dogs. In the case of Neo-CoV, sequence analysis of the S protein suggests that intraspecies recombination events might have given rise to MERS-CoV.  In this scenario, the import of dromedary camels from the Horn of Africa to the Arabian peninsula might have inadvertently caused MERS.

The identification of the cellular receptor, hDPP4, and the viral Receptor binding domain (RBD) within the S1 subunit of the viral S protein lead to the development of monoclonal antibodies. One of the mAb tested, m336, neutralised both live and pseudotyped MERS-CoV with an exceptional potency of ID50 (half maximal inhibitory concentration) of 0.005 (pseudotyped MERS-CoV) and 0.07  (live MERS-CoV) μg/ml, respectively, by competing with the hDPP4 receptor. Monoclonal antibodies however do not constitute a vaccination but an antiviral. In the case of MERS-CoV, the first problem in developing a vaccine is if this vaccine is intended for the use in humans or animal (namely dromedary camels). While the disease is severe in humans, dromedary camels seem only to show mild symptoms if any at all and infection seems predominantly occur in calfs rather than adult animals. For obvious reasons, testing the efficiency and safety of vaccines in dromedary camels is a difficult task. Nevertheless, any MERS-CoV vaccine has to take into account that those people at risk for MERS are first and foremost those people handling dromedary camels - anywhere from veterinaries to farmers, farm workers, and their families. Having said so, we shall now discuss recent developments in finding a MERS-CoV vaccine.

As discussed before in a previous post, one strategy is to generate a MERS-CoV pseudovirus, which can be used to infect target cells and generate an immune response. In the case of MERS-CoV -and indeed all Coronaviridae- the viral S protein mediates cell entry via binding the cellular receptor through the RBD located within the S1- subunit as well as the Fusion peptide located within the N-terminus of the S2 subunit and a truncated fragment of the MERS-CoV S1 containing the RBD fused with human IgG Fc fragment (S377-588-Fc) not only prevents MERS-CoV infection of cell lines but also elicits a high antibody titre in rabbits and mice infected with MERS-CoV.  In contrast to fusion petides, the use replication deficient viruses such as pseudotyped Vaccinia Virus strain Ankara or recombinant replication deficient Adenovirus Type 5 (rAd5) expressing MERS-CoV S or the MERS-CoV S1 subunit allows for the induction of the highly efficient mucosal cell immune response, thus mimicking a natural infection. Indeed, the application of a recombinant Vaccinia Virus strain Ankara expressing MERS-CoV S (r)Ad5.MERS-S and (r)Ad5.MERS-S1 (1-725) elicit high antibody titres in mice. As mentioned above, to test if the recombinant viruses also work in dromedary camels is going to be difficult, but studies done using the dromedary camel cell line Dubca3 and peripheral blood mononuclear cells (PBMC) from isolated from camels suggest that a recombinant Ad5 expressing EGFP rAd5.EGFP) can infect both cell lines. Although sera from mice infected with either (r)Ad5.MERS-S and (r)Ad5.MERS-S1 neutralises MERS-CoV infection of Vero cells, a similar effect on infection of Dubca cells or camel derived PBMC with either human, bat, or dromedary camel derived MERS-CoV has not been demonstrated.
Adenovirus based vaccines however cannot be used in humans because of the high prevalence of neutralising antibodies. Dromedary camels however seem to be negative for antibodies against Ad5, so it is possible to use a Adenovirus based vaccine in animals. As discussed above, vaccinating animals at birth might a feasible approach. One might also consider that countries affected by MERS should stop importing dromedary camels that have been caught in the wild and instead only import those born and raised on farms.

Constructs used in generating antigenic peptides or vaccine candidates

Further reading

Abroug F, Slim A, Ouanes-Besbes L, Kacem MA, Dachraoui F, Ouanes I, Lu X, Tao Y, Paden C, Caidi H, Miao C, Al-Hajri MM, Zorraga M, Ghaouar W, BenSalah A, Gerber SI, & World Health Organization Global Outbreak Alert and Response Network Middle East Respiratory Syndrome Coronavirus International Investigation Team (2014). Family cluster of middle East respiratory syndrome coronavirus infections, Tunisia, 2013. Emerging infectious diseases, 20 (9), 1527-30 PMID: 25148113

Reusken CB, Messadi L, Feyisa A, Ularamu H, Godeke GJ, Danmarwa A, Dawo F, Jemli M, Melaku S, Shamaki D, Woma Y, Wungak Y, Gebremedhin EZ, Zutt I, Bosch BJ, Haagmans BL, & Koopmans MP (2014). Geographic distribution of MERS coronavirus among dromedary camels, Africa. Emerging infectious diseases, 20 (8), 1370-4 PMID: 25062254

Corman VM, Jores J, Meyer B, Younan M, Liljander A, Said MY, Gluecks I, Lattwein E, Bosch BJ, Drexler JF, Bornstein S, Drosten C, & Müller MA (2014). Antibodies against MERS coronavirus in dromedary camels, Kenya, 1992-2013. Emerging infectious diseases, 20 (8), 1319-22 PMID: 25075637 

Corman VM, Ithete NL, Richards LR, Schoeman MC, Preiser W, Drosten C, & Drexler JF (2014). Rooting the phylogenetic tree of middle East respiratory syndrome coronavirus by characterization of a conspecific virus from an african bat. Journal of virology, 88 (19), 11297-303 PMID: 25031349

Chan RW, Hemida MG, Kayali G, Chu DK, Poon LL, Alnaeem A, Ali MA, Tao KP, Ng HY, Chan MC, Guan Y, Nicholls JM, & Peiris JS (2014). Tropism and replication of Middle East respiratory syndrome coronavirus from dromedary camels in the human respiratory tract: an in-vitro and ex-vivo study. The Lancet. Respiratory medicine PMID: 25174549 

Al-Tawfiq JA, & Memish ZA (2014). Middle East respiratory syndrome coronavirus: transmission and phylogenetic evolution. Trends in microbiology PMID: 25178651 

Ying T, Du L, Ju TW, Prabakaran P, Lau CC, Lu L, Liu Q, Wang L, Feng Y, Wang Y, Zheng BJ, Yuen KY, Jiang S, & Dimitrov DS (2014). Exceptionally potent neutralization of Middle East respiratory syndrome coronavirus by human monoclonal antibodies. Journal of virology, 88 (14), 7796-805 PMID: 24789777 

Jiang L, Wang N, Zuo T, Shi X, Poon KM, Wu Y, Gao F, Li D, Wang R, Guo J, Fu L, Yuen KY, Zheng BJ, Wang X, & Zhang L (2014). Potent neutralization of MERS-CoV by human neutralizing monoclonal antibodies to the viral spike glycoprotein. Science translational medicine, 6 (234) PMID: 24778414 

Kim E, Okada K, Kenniston T, Raj VS, AlHajri MM, Farag EA, AlHajri F, Osterhaus AD, Haagmans BL, & Gambotto A (2014). Immunogenicity of an adenoviral-based Middle East Respiratory Syndrome coronavirus vaccine in BALB/c mice. Vaccine PMID: 25192975 

Yang L, Wu Z, Ren X, Yang F, Zhang J, He G, Dong J, Sun L, Zhu Y, Zhang S, & Jin Q (2014). MERS-related betacoronavirus in Vespertilio superans bats, China. Emerging infectious diseases, 20 (7), 1260-2 PMID: 24960574 

Wang Q, Qi J, Yuan Y, Xuan Y, Han P, Wan Y, Ji W, Li Y, Wu Y, Wang J, Iwamoto A, Woo PC, Yuen KY, Yan J, Lu G, & Gao GF (2014). Bat Origins of MERS-CoV Supported by Bat Coronavirus HKU4 Usage of Human Receptor CD26. Cell host & microbe, 16 (3), 328-37 PMID: 25211075

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