A recombinant VSV-vectored MERS-CoV vaccine induces neutralizing antibody and T cell responses in rhesus monkeys after single dose immunization

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) has been a highly threatening zoonotic pathogen since its outbreak in 2012. Similar to SARS-CoV, MERS-CoV belongs to the coronavirus family and can induce severe respiratory symptoms in humans, with an average case fatality rate of 35% according to the World Health Organization. Spike (S) protein of MERS-CoV is immunogenic and can induce neutralizing antibodies, thus is a potential major target for vaccine development. Here we constructed a chimeric virus based on the vesicular stomatitis virus (VSV) in which the G gene was replaced by MERS-CoV S gene (VSVΔG-MERS). The S protein efficiently incorporated into the viral envelope and mediated cell entry through binding its receptor, human DPP4. Knockdown of clathrin expression by siRNA drastically abrogated the infection of VSVΔG-MERS in Vero cells. Furthermore, in animal studies, the recombinant virus induced neutralizing antibodies and T cell responses in rhesus monkeys after a single intramuscular or intranasal immunization dose. Our findings indicate the potential of the chimeric VSVΔG-MERS as a rapid response vaccine candidate against emerging MERS-CoV disease.

Recombinant vesicular stomatitis virus vector vaccines for WHO blueprint priority pathogens

“…In an analogous manner, VSVΔG was later used to create a MERS-CoV vaccine by expressing the MERS-CoV spike protein (S), and VSVΔG-MERS displayed immunogenicity in rhesus monkeys. 118 To date, no human clinical trials have been reported for VSV-based CoV vaccines and the WHO roadmap for MERS-CoV research and product development does not currently include rVSV-vectored vaccines in the port-folio of vectored vaccines. 119 Zika virus rVSV vectors have also been employed in designing vaccine candidates against Zika virus (ZIKV), a flavivirus closely related to Dengue, West-Nile, Japanese encephalitis and Yellow Fever viruses, which has been associated with severe neurological disorders such as microcephaly in newborns and Guillan-Barré Syndrome.…”

MERS coronavirus outbreak: Implications for emerging viral infections

“…We have recently extensively reviewed candidate MERS-CoV therapies and vaccines (Rabaan et al, 2017). Table 2 shows a summary of current and proposed therapies and vaccines, including targets, advantages and disadvantages, updated to include some potential agents that have emerged since the publication of our review (Alharbi et al, 2017;Jung et al, 2018;Langenmayer et al, 2018;Li et al, 2018;Liu et al, 2018;Niu et al, 2018;Rabaan et al, 2017;Sun et al, 2017). Development of a targeted anti-MERS-CoV therapy and availability of effective vaccines would require coordinated efforts to carry out properly controlled and organized clinical trials.…”

“…T cell and neutralizing antibody responses (Liu et al, 2018) Chimpanzee adenovirus (ChAdOx1) expressing full-length S…”

“…Availability of monoclonal antibodies may be of particular use in outbreak situations, which continue to arise in KSA. Other potential S protein-targeting vaccine candidates include nanoparticles expressing full-length S protein and active immunization strategies using vectors including modified vaccinia, adenoviruses or measles viruses or plasmids expressing full-length S protein as potential vaccine candidates, discussed in more detail in the next section (Alharbi et al, 2017;Guo et al, 2015;Inovio, 2016;Jung et al, 2018;Langenmayer et al, 2018;Liu et al, 2018;Malczyk et al, 2015;Muthumani et al, 2015;Volz et al, 2015). Antiviral peptides that target the HR2 regions of the S protein and hence virus-host cell fusion have also been shown to have potential therapeutic activities in cell culture and transgenic animal studies (Bosch et al, 2004;Channappanavar et al, 2015;Liu et al, 2004Liu et al, , 2014b.…”

“…As with therapy development, the S protein is the focus of many candidate vaccines (Alharbi et al, 2017;Coleman et al, 2014;Guo et al, 2015;Inovio, 2016;Jung et al, 2018;Langenmayer et al, 2018;Liu et al, 2018;Malczyk et al, 2015;Muthumani et al, 2015;Volz et al, 2015). Vectors including modified vaccinia virus Ankara (MVA), ad5 or ad41-type adenoviruses, measles virus, chimeric vesicular stomatitis virus (VSV) and chimpanzee adenovirus (ChAdOx1) have been successfully used to express MERS-CoV S protein and induce neutralizing antibodies in mice and in other animal models including camels and rhesus monkeys ( Table 2) (Alharbi et al, 2017;Coleman et al, 2014;Guo et al, 2015;Inovio, 2016;Jung et al, 2018;Langenmayer et al, 2018;Liu et al, 2018;Malczyk et al, 2015;Muthumani et al, 2015;Volz et al, 2015). These virus vectors have the advantage of good safety profiles in humans.…”