Two-mAb cocktail prevents SARS-CoV-2 infection, study suggests

A promising study shows that a combination of two monoclonal antibodies effectively neutralized the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in monkeys and proved efficacious against newer variants of concern in vitro. This could help develop preventive pharmacological measures against the spread of the virus to susceptible contacts.

Study: A combination of two human neutralizing antibodies prevents SARS-CoV-2 infection in rhesus macaques. Image Credit: Kateryna Kon/ Shutterstock

Background

The ongoing pandemic of coronavirus disease 2019 (COVID-19) has caused many cases and deaths worldwide. The virus engages the human angiotensin-converting enzyme 2 (ACE2) receptor on the host cell to gain entry into the cell and establish infection. The viral spike protein is responsible for this binding and is thus the target of most neutralizing antibodies.

The spike protein exists in different conformations, including open and closed conformations for the receptor-binding domain (RBD) that contacts ACE2. The RBD is on the S1 subunit of the spike, while the S2 subunit contains the fusion peptide that triggers the fusion of the host cell membranes and the virus, allowing the virus to enter the cell.

Earlier studies showed that the most potent neutralizing antibodies to the virus target the RBD after natural infection or vaccination. Passive immunity via a high dose of monoclonal antibodies (mAbs) directed against the ACE2 receptor was shown to protect a non-human primate (NHP) model against SARS-CoV-2 infection.

Currently available antibodies that have received emergency use authorization from the US Food and Drug Administration (FDA) have not been approved for preventive use, but this could help protect high-risk individuals from the infection if they cannot mount an adequate immune response by vaccination for any reason.

The current study looked at the efficacy of two human mAbs in preventing SARS-CoV-2 infection when given at low to moderate doses. These antibodies bind to distinct RBD epitopes and thus minimize the risk of immune escape mutations when given in combination.

The mAbs studied were COV2-2381 and COV2-2130. The former binds to the receptor-binding motif on the RBD on one of the spike protomers in the open conformation. The other binds to another site on the RBD in either the closed or open state.

The antibodies were modified for resistance to degradation with the YTE triplet mutation on the Fc portion. This also reduced Fcγ receptor binding, thus reducing Fc-mediated effector activity. The resulting efficacy would thus owe nothing to Fc-mediated effects, being due only to the neutralization of the spike antigen.

The aim was to determine the level of serum neutralizing activity that would allow effective neutralization. A preprint version of the study is available on the bioRxiv* server while the article undergoes peer review.

What did the study show?

The findings indicate that the two-mAb cocktail, called ADM03820, prevents SARS-CoV-2 infection of the lungs and nasopharynx following challenge with the virus in a dose-dependent fashion.

The cocktail could be given intravenously or intramuscularly. This was followed by the successful detection of the antibodies at the sites of infection with the virus. The detected concentrations ranged from 10 ng/mL to 270 ng/mL, even in specimens of nasal washes which involve antibody dilution.

The circulating human mAbs were present at high titers in serum on the day of administration, at a median level of 193 μg/mL after IM or 520 μg/mL after IV administration. Thereafter, the serum levels declined slowly over three months, to 9 μg/mL on day 84 after IM or 26 μg/mL after IV administration.

The cocktail powerfully neutralized SARS-CoV-2 variants of concern. This included variants with the D614G mutation, the alpha or B.1.1.7 virus, the delta or B.1.617.2 virus, and chimeric viruses containing the spike gene from the beta strain B.1.351 or B.1.1.28. The prolonged persistence of the antibodies in serum and mucosa at adequate concentrations indicated the ability to neutralize the variants now circulating.

NHPs treated with the antibody cocktail and then challenged with the virus did not show evidence of viral replication. Most monkeys cleared the virus by day 2. The effect was similar for individual antibodies. At the lowest dose, breakthrough infection occurred due to the inadequate levels of neutralizing antibodies.

The lowest protective dose of the cocktail was found by graduating the doses of the combination across four treatment groups intramuscularly. The decline in titer of neutralizing antibodies correlated with the administered dose in all four treated groups of animals.

The animals treated with the cocktail of antibodies were apparently protected against lung infection with the virus at all doses. In contrast, the nasopharyngeal mucosa showed increasing viral loads at lower doses. Higher antibody doses seem to be required to regulate viral replication in the upper respiratory tract.

The protective threshold in lung and nasal washings was estimated at 20 μg/mL or more for circulating antibodies and a half-maximal neutralizing antibody titer (NT50) of 6,000 or more. These levels correlated to complete protection against infection in up to 93% of NHPs when challenged with the virus, compared to less than half the animal's given antibodies below these levels.

What are the implications?

The researchers found that neutralizing activity alone was responsible for a high degree of protection and offered a threshold for protective neutralizing activity. This type of calculation is important in providing a mechanistic link to protection via neutralization, helping to find the duration over which administered antibodies can help protect the individual against infection.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.