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. 2015 Aug 18;2(10):1438-46.
doi: 10.1016/j.ebiom.2015.08.031. eCollection 2015 Oct.

Recombinant Receptor Binding Domain Protein Induces Partial Protective Immunity in Rhesus Macaques Against Middle East Respiratory Syndrome Coronavirus Challenge

Jiaming Lan  1 , Yanfeng Yao  2 , Yao Deng  3 , Hong Chen  3 , Guangwen Lu  4 , Wen Wang  3 , Linlin Bao  2 , Wei Deng  2 , Qiang Wei  2 , George F Gao  4 , Chuan Qin  2 , Wenjie Tan  3
Affiliations

Recombinant Receptor Binding Domain Protein Induces Partial Protective Immunity in Rhesus Macaques Against Middle East Respiratory Syndrome Coronavirus Challenge

Jiaming Lan et al. EBioMedicine. .

Erratum in

Abstract

Background: Development an effective vaccine against Middle East respiratory syndrome coronavirus (MERS-CoV) is urgent and limited information is available on vaccination in nonhuman primate (NHP) model. We herein report of evaluating a recombinant receptor-binding domain (rRBD) protein vaccine in a rhesus macaque model.

Methods: Nine monkeys were randomly assigned to high-dose, low-dose and mock groups,which were immunized with different doses of rRBD plus alum adjuvant or adjuvant alone at different time points (0, 8, 25 weeks). Immunological analysis was conducted after each immunisation. Monkeys were challenged with MERS-CoV at 14 days after the final immunisation followed by observation for clinical signs and chest X-rays. Nasal, oropharyngeal and rectal swabs were also collected for analyses. Monkeys were euthanized 3 days after challenge and multiple specimens from tissues were collected for pathological, virological and immunological tests.

Conclusion: Robust and sustained immunological responses (including neutralisation antibody) were elicited by the rRBD vaccination. Besides, rRBD vaccination alleviated pneumonia with evidence of reduced tissue impairment and clinical manifestation in monkeys. Furthermore, the rRBD vaccine decreased viral load of lung, trachea and oropharyngeal swabs of monkeys. These data in NHP paves a way for further development of an effective human vaccine against MERS-CoV infection.

Keywords: Immunity; MERS-CoV; Protection; RBD; Rhesus macaque; Vaccine.

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Figures

Fig. 1
Fig. 1
Schematic diagram of the rRBD vaccination and MERS-CoV challenge schedule. Monkeys were immunised three times intramuscularly (i.m.), at intervals of 8 or 17 weeks, and inoculated intratracheally with hCoV-EMC at a dosage of 6.5 × 107 TCID50 (red arrow). Monkeys were bled periodically at 2, 10, and 25 weeks (− 14 days), and at − 1 day, 1 day and 3 days. Additionally, nasal, oral and rectal swabs were collected at − 1 day, 1 day and 3 days. Chest X-rays were performed 1 day before inoculation, and at 1 and 3 dpi. Following euthanasia, lung, trachea, spleen and kidney specimens of challenged monkeys were acquired at 3 dpi for detection.
Fig. 2
Fig. 2
Humoral and cellular immune responses induced by rRBD vaccination. a. RBD-specific IgG antibody titres at the indicated time points after vaccine inoculation were monitored by ELISA. b–d. Neutralisation antibody titres in the sera of immunised rhesus macaques 2 weeks after the second vaccination; long-term observation (17-weeks) and the subsequent (i.e. third) vaccination booster were detected using a pseudovirus neutralisation system. e. Sera neutralisation antibodies were detected on Vero cells. f. ELISpot analysis of rhesus macaques PBMCs derived at the indicated time points after rRBD immunisation. All of the detections were replicated for three times. *p < 0.01 and **p < 0.01.
Fig. 3
Fig. 3
Radiographic alterations and lung pathology. a. X-rays from rhesus macaques imaged prior to (− 1 day) and post-MERS-CoV inoculation (1 day and 3 days). Areas of interstitial infiltration, indicative of pneumonia, are highlighted (circle). b. Gross pathology of the lungs from necropsied animals at 3 dpi. Haemorrhage and necrosis indicated by the black circle in both high and low dose immunisation groups were small and local, which happened in the mock group were large and disperse. M, H and L represent the mock, high- and low-dose groups, respectively.
Fig. 4
Fig. 4
Histopathological changes in the lungs and tracheas of immunised rhesus macaques following MERS-CoV challenge. Three days after MERS-CoV inoculation, all monkeys were euthanised. Tissues were collected and stained with haematoxylin and eosin (H & E). a–f. Pathological changes in the lungs of immunised monkeys. The black triangle indicates acute interstitial pneumonia diffused in lung tissue. The unfilled arrow indicates the hyaline member resulting from effusion of fibrin. The black arrow indicates the influx of inflammatory cells. g–i. Pathological findings of tracheas in immunised rhesus macaques. The black arrow highlights the infiltration of inflammatory cells in the tunica mucosa bronchiorum. The unfilled arrow indicates epithelium impairment in tunica mucosa bronchiorum. M, H and L represent the mock, high- and low-dose groups, respectively.
Fig. 5
Fig. 5
IHC staining of immunised rhesus macaque lung and trachea 3 days after MERS-CoV infection by a polyclonal antibody against nucleoprotein. a–c. IHC analysis of lung tissue. d–f. IHC staining of trachea tissue. Black arrows indicate the distribution of viral antigen. M, H and L represent mock, high- and low-dose groups, respectively.
Fig. 6
Fig. 6
MERS-CoV loads in the swabs and tissues of immunised rhesus macaques following MERS-CoV infection detected by Real-time-PCR. a. Viral loads in swab samples at 1 dpi and 3 dpi. b. The viral loads in lung and trachea tissue 3 days after MERS-CoV infection. All of the detections were replicated for three times. M, H and L represent mock, high- and low-dose groups, respectively. *p < 0.05.
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References

    1. Agrawal A.S., Garron T., Tao X., Peng B., Wakamiya M., Chan T., Couch R.B., Tseng C.K. Generation of a transgenic mouse model of middle east respiratory syndrome coronavirus infection and disease. J. Virol. 2015;89(7):3659–3670. - PMC - PubMed
    1. Annan A., Baldwin H.J., Corman V.M., Klose S.M., Owusu M., Nkrumah E.E., Badu E.K., Anti P., Agbenyega O., Meyer B., Oppong S., Sarkodie Y.A., Kalko E.K.V., Lina P.H.C., Godlevska E.V., Reusken C., Seebens A., Gloza-Rausch F., Vallo P., Tschapka M., Drosten C., Drexler J.F. Human betacoronavirus 2c EMC/2012–related viruses in bats, Ghana and Europe. Emerg. Infect. Dis. 2013;19(3):456–459. - PMC - PubMed
    1. Anthony S.J., Ojeda-Flores R., Rico-Chavez O., Navarrete-Macias I., Zambrana-Torrelio C.M., Rostal M.K., Epstein J.H., Tipps T., Liang E., Sanchez-Leon M., Sotomayor-Bonilla J., Aguirre A.A., Avila-Flores R., Medellin R.A., Goldstein T., Suzan G., Daszak P., Lipkin W.I. Coronaviruses in bats from Mexico. J. Gen. Virol. 2013;94(Pt_5):1028–1038. - PMC - PubMed
    1. Coleman C.M., Matthews K.L., Goicochea L., Frieman M.B. Wild-type and innate immune-deficient mice are not susceptible to the Middle East respiratory syndrome coronavirus. J. Gen. Virol. 2014;95(Pt_2):408–412. - PMC - PubMed
    1. Corman V.M., Muller M.A., Costabel U., Timm J., Binger T., Meyer B., Kreher P., Lattwein E., Eschbach-Bludau M., Nitsche A., Bleicker T., Landt O., Schweiger B., Drexler J.F., Osterhaus A.D., Haagmans B.L., Dittmer U., Bonin F., Wolff T., Drosten C. Assays for laboratory confirmation of novel human coronavirus (hCoV-EMC) infections. Euro Surveill. 2012;17(49) - PubMed

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