Monoclonal antibody therapy demonstrates increased virulence of a lineage VII strain of Lassa virus in nonhuman primates

ABSTRACT

Lassa virus (LASV) is a World Health Organization (WHO) priority pathogen that causes high morbidity and mortality. Recently, we showed that a combination of three broadly neutralizing human monoclonal antibodies known as Arevirumab-3 (8.9F, 12.1F, 37.2D) based on the lineage IV Josiah strain protected 100% of cynomolgus macaques against heterologous challenge with lineage II and III strains of LASV when therapy was initiated beginning at day 8 after challenge. LASV strains from Benin and Togo represent a new lineage VII that are more genetically diverse from lineage IV than strains from lineages II and III. Here, we tested the ability of Arevirumab-3 to protect macaques against a LASV lineage VII Togo isolate when treatment was administered beginning 8 days after exposure. Unexpectedly, only 40% of treated animals survived challenge. In a subsequent study we showed that Arevirumab-3 protected 100% of macaques from lethal challenge when treatment was initiated 7 days after LASV Togo exposure. Based on our transcriptomics data, successful Arevirumab-3 treatment correlated with diminished neutrophil signatures and the predicted development of T cell responses. As the in vitro antiviral activity of Arevirumab-3 against LASV Togo was equivalent to lineage II and III strains, the reduced protection in macaques against Togo likely reflects the faster disease course of LASV Togo in macaques than other strains. This data causes concern regarding the ability of heterologous vaccines and treatments to provide cross protection against lineage VII LASV isolates.

KEYWORDS:

• Lassa virus
• arenavirus
• monoclonal antibodies
• haemorrhagic fever
• nonhuman primates

Acknowledgements

The authors would like to thank the UTMB Animal Resource Center for husbandry support of laboratory animals. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the University of Texas Medical Branch.

Disclosure statement

LMB, RFG, and TWG are named on a provisional World International Property Organization patent entitled “Arenavirus Monoclonal Antibodies and Uses” (International publication number WO 2018/106712 A1 filed on 14 June 2018) and on a US Patent application entitled “Arenavirus Monoclonal Antibodies and Uses” (Publication number US 2022/0089696 A1 filed on 24 March 2022). LMB and RFG are co-founders of Zalgen Labs. LMB receives compensation from Zalgen Labs. RFG does not receive compensation from Zalgen Labs. LMB and MLH are employed by Zalgen Labs and receive compensation from the company. The other authors declare no competing interests.

Data availability

All study data are included in the main text or the supporting information.

Author contributions

RWC and TWG conceived and designed the model development study. RWC, RFG, LMB, and TWG conceived and designed the antibody treatment studies. MLH characterized and validated the antibodies. DJD challenged and treated the animals and performed phlebotomy and euthanasia. RWC assisted with the challenges and performed phlebotomy and euthanasia. CW and ANP assisted with the treatments and performed phlebotomy and euthanasia. RWC, CW, ANP, DJD, MBH, and TWG conducted clinical observations of the animals. VB, KNA, and ANP performed the clinical pathology assays. VB performed the LASV infectivity assays. KNA developed and optimized the PCR assay for LASV Togo and performed the PCR assays. CW performed the NanoString assays. NSD performed the IHC assays. KAF performed histological and immunohistochemical analysis of the data. All authors analyzed the data. TWG wrote the paper with additions from CW, ANP, and KAF. RWC edited the paper. ANP and CW prepared the figures. TWG prepared the tables. All authors had access to all of the data and approved the final version of the manuscript.

Competing interests

LMB, RFG, and TWG are named on a provisional World International Property Organization patent entitled “Arenavirus Monoclonal Antibodies and Uses” (International publication number WO 2018/106712 A1 filed on 14 June 2018) and on a US Patent application entitled “Arenavirus Monoclonal Antibodies and Uses” (Publication number US 2022/0089696 A1 filed on 24 March 2022). LMB and RFG are co-founders of Zalgen Labs. LMB receives compensation from Zalgen Labs. RFG does not receive compensation from Zalgen Labs. LMB is employed by Zalgen Labs and receive compensation from the company. The other authors declare no competing interests.

Additional information

Funding

This study was supported by the Department of Health and Human Services, National Institutes of Health (NIH) grants R01AI132223 and U19AI142790 to RFG, UTMB Department of Microbiology and Immunology funds to TWG, and National Institutes of Health grant number UC7AI094660 for BSL-4 operations support of the Galveston National Laboratory.