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. 2021 Dec;10(1):2194-2198.
doi: 10.1080/22221751.2021.2002670.

Waning antibodies from inactivated SARS-CoV-2 vaccination offer protection against infection without antibody-enhanced immunopathology in rhesus macaque pneumonia models

Dandan Li  1 , Ning Luan  1 , Jing Li  1 , Heng Zhao  1 , Ying Zhang  1 , Runxiang Long  1 , Guorun Jiang  1 , Shengtao Fan  1 , Xingli Xu  1 , Han Cao  1 , Yunfei Wang  1 , Yun Liao  1 , Lichun Wang  1 , Longding Liu  1 , Cunbao Liu  1 , Qihan Li  1
Affiliations

Waning antibodies from inactivated SARS-CoV-2 vaccination offer protection against infection without antibody-enhanced immunopathology in rhesus macaque pneumonia models

Dandan Li et al. Emerg Microbes Infect. 2021 Dec.

Abstract

Inactivated coronaviruses, including severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV), as potential vaccines have been reported to result in enhanced respiratory diseases (ERDs) in murine and nonhuman primate (NHP) pneumonia models after virus challenge, which poses great safety concerns of antibody-dependent enhancement (ADE) for the rapid wide application of inactivated SARS-CoV-2 vaccines in humans, especially when the neutralizing antibody levels induced by vaccination or initial infection quickly wane to nonneutralizing or subneutralizing levels over the time. With passive transfer of diluted postvaccination polyclonal antibodies to mimic the waning antibody responses after vaccination, we found that in the absence of cellular immunity, passive infusion of subneutralizing or nonneutralizing anti-SARS-CoV-2 antibodies could still provide some level of protection against infection upon challenge, and no low-level antibody-enhanced infection was observed. The anti-SARS-CoV-2 IgG-infused group and control group showed similar, mild to moderate pulmonary immunopathology during the acute phase of virus infection, and no evidence of vaccine-related pulmonary immunopathology enhancement was found. Typical immunopathology included elevated MCP-1, IL-8 and IL-33 in bronchoalveolar lavage fluid; alveolar epithelial hyperplasia; and exfoliated cells and mucus in bronchioles. Our results corresponded with the recent observations that no pulmonary immunology was detected in preclinical studies of inactivated SARS-CoV-2 vaccines in either murine or NHP pneumonia models or in large clinical trials and further supported the safety of inactivated SARS-CoV-2 vaccines.

Keywords: ADE; SARS-CoV-2; immunopathology; inactivated vaccines; subneutralizing antibodies.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Protection against infection upon SARS-CoV-2 challenge provided by waning antibodies from inactivated SARS-CoV-2 vaccination in rhesus macaques. (a) Scheme of the experimental design. (b) Serum neutralizing antibody (NAb) geometric mean titres (GMTs) before and after virus challenge. Each point represents one animal. A titre of neutralizing antibodies less than 1:4 was designated negative (value = 1) in the GMT calculation. (c) Viral loads at the indicated time points (for nasal swabs and pharyngeal swabs, each line represents one animal) and on sacrifice day (for different tissues, the results for each group are presented as means ± SDs). A viral copy number of less than 50copies/100μl or 50copies/100 mg (dotted lines) was considered negative. (d) Proinflammatory mediator concentrations in bronchoalveolar lavage fluid (BALF) on the sacrifice day. Duplicate wells were performed in all experiments, each point represents average value for duplicate wells. (e) Pathology score. The average estimated severity of the lesions was determined by two pathologists in at least five areas at 100x as well as 200× magnification and scored as 1 (weak), 2 (moderate) or 3 (severe); and the total score was calculated by adding the scores of the left & right lung and superior & inferior lobe of each animal. Each point represents one animal. (f) Pathological indicators of each animal lung tissue with H&E staining. (g) Normal alveoli. (h) Mild alveolar epithelial hyperplasia. (i) Moderate alveolar epithelial hyperplasia. (j) Eosinophil infiltration indicated by arrows. (k) Alveolar epithelial congestion. (l) Alveolar epithelial oedema. (m) Normal bronchioles. (n) Exfoliated cells in bronchioles. (o) Mucus and exfoliated cells in bronchioles. All of the bars in the low right corner=100 µm except for that in Figure 1j, which is 50 μm. Two-way ANOVA was used for the viral loads on sacrifice day for different tissues to compare the difference between the experiment and control group (c). The t test was used for the ELISA and pathology score to compare the difference between the experiment and control group (d and e). ***p < 0.001 versus the control group.
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Grants and funding

This work was supported by the National Key R&D Program of China (grant numbers 2020YFC0849700 and 2020YFC0860600), the Major Science and Technology Special Projects of Yunnan Province (grant numbers 202003AC100003, 202002AA100009 and 202102AA310043), Special Biomedicine Projects of Yunnan Province (202102AA310035), Basic Research Projects of Yunnan Province (202101AT070286) and Funds for the Training of High-level Health Technical Personnel in Yunnan Province, China (grant number H-2019063).

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