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. 2024 Aug 21;9(2):79-93.
doi: 10.20411/pai.v9i2.718. eCollection 2024.

Impact of SARS-CoV-2 Resistance to Antiviral Monoclonal Antibody Therapy on Neutralizing Antibody Response

Marc-Kendy Paul  1 , Manish C Choudhary  1 , Amy L Heaps  2 , Rinki Deo  1 , Daniela Moisi  3 , Kelley C Gordon  2 , John W Mellors  2 , Carlee Moser  4 , Paul Klekotka  5 , Alan Landay  6 , Judith S Currier  7 , Joseph J Eron  8 , Kara W Chew  7 , Davey M Smith  9 , Scott F Sieg  10 , Urvi M Parikh  2 , Jonathan Z Li  1 ; ACTIV-2/A5401 Study Team
Affiliations

Impact of SARS-CoV-2 Resistance to Antiviral Monoclonal Antibody Therapy on Neutralizing Antibody Response

Marc-Kendy Paul et al. Pathog Immun. .

Abstract

Background: Anti-SARS-CoV-2 monoclonal antibodies (mAbs) have played a key role as an anti-viral against SARS-CoV-2, but there is a potential for resistance to develop. The interplay between host antibody responses and the development of monoclonal antibody (mAb) resistance is a critical area of investigation. In this study, we assessed host neutralizing antibody (nAb) responses against both ancestral virus and those with treatment-emergent E484K bamlanivimab resistance mutations.

Methods: Study participants were enrolled in the ACTIV-2/Advancing Clinical Therapeutics Globally (ACTG) A5401 phase 2 randomized, placebo-controlled trial of bamlanivimab 700 mg mAb therapy (NCT04518410). Anterior nasal and nasopharyngeal swabs were collected for SARS-CoV-2 RNA testing and S gene next-generation sequencing to identify the E484K bamlanivimab resistance mutation. Serum nAb titers were assessed by pseudovirus neutralization assays.

Results: Higher baseline (pre-treatment) nAb titers against either ancestral or E484K virus was associated with lower baseline viral load. Participants with emerging resistance had low levels of nAb titers against either ancestral or E484K nAb at the time of study entry. Participants with emergent E484K resistance developed significantly higher levels of E484K-specific nAb titers compared to mAb-treated individuals who did not develop resistance. All participants who developed the E484K mAb resistance mutation were eventually able to clear the virus.

Conclusion: Emerging drug resistance after SARS-CoV-2-specific mAb therapy led to a heightened host neutralizing antibody response to the mAb-resistant variant that was associated with eventual viral clearance. This demonstrates the interplay between the antiviral treatment-directed viral evolution and subsequent host immune response in viral clearance.

Keywords: COVID-19; SARS-CoV-2; bamlanivimab; monoclonal antibody; pseudovirus neutralization.

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Conflict of interest statement

UMP has consulted for Merck unrelated to the current work. JWM is a consultant for and receives grant support from Gilead Sciences, unrelated to the current work. JZL has consulted for Abbvie and received research support from Merck unrelated to the current work. KWC has consulted for Pardes Biosciences. DMS has consulted for Bayer Pharmaceuticals, Linear Therapies, Model Medicines, FluxErgy, and Vx Biosciences. ALL has consulted for Gilead and Abbott.

Figures

Figure 1.
Figure 1.
Comparison of log10 NT50 values in different study groups at study entry. (A) against ancestral virus, (B) against E484K virus. The boxplots represent the 25th and 75th percentiles (bottom and top edge of the box), while the open circles represent individual data point. Median values are represented by horizontal line within the boxplot. Comparison of NT50 values across study groups were compared using Wilcoxon rank sum test. P<0.05 were considered statistically significant.
Figure 2.
Figure 2.
Figures illustrate the viral loads and frequencies of primary resistance mutations from anterior nasal swab (AN) samples in 5 different participants exhibiting primary bamlanivimab resistance mutations. The wild-type and resistance mutations are represented by colored bars, indicating different types of changes. The SARS-CoV-2 viral load is depicted with a solid blue line. Neutralizing antibody (nAb) values at baseline and on day 28 for the wild-type and E484K mutations are shown with green and red dotted lines, respectively. The outer and inner left y-axes represent nAb values and viral load in log10 copies/mL, while the right y-axis indicates amino acid frequency.
Figure 3.
Figure 3.
Comparison of NT50 fold change w.r.t. study entry against E484K virus in different study groups. Boxplot shows NT50 fold change at day 28 w.r.t. study entry in different study groups against E484K virus. The boxplots represent the 25th and 75th percentiles (bottom and top edge of the box), while the open circles represent individual data point. Median values are represented by horizontal line within the boxplot. Comparison of median values across study groups were compared using Wilcoxon rank sum test. P<0.05 were considered statistically significant.
See this image and copyright information in PMC

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