Vaccine research continues to provide safe, effective, and durable protection against the coronavirus disease 2019 (COVID-19) pandemic. A new study on the medRxiv* server reports long-lasting, effective protection against severe disease with the AZD7442 antibody cocktail.
Study: AZD7442 demonstrates prophylactic and therapeutic efficacy in non-human primates and extended half-life in humans. Image Credit: Kateryna Kon/Shutterstock
A preprint version of the study is available on the medRxiv* server while the article undergoes peer review.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered a pandemic that shut down businesses and schools worldwide and severely restricted routine social interactions for months.
An effective route of treatment was shown to be monoclonal antibodies. These are therapeutics based on potent neutralizing antibodies derived from human plasma, which were refined to those generated by a single plasma cell and therefore capable of recognizing and binding to a single epitope on the viral spike protein receptor-binding domain (RBD).
Many remain at risk of severe illness and death due to COVID-19, including the risk to those who are immunocompromised and those who develop breakthrough infections.
The spike RBD is responsible for viral engagement with the host cell human angiotensin-converting enzyme 2 (ACE2) receptor and for viral entry into the cell to establish infection. Antibodies that target the spike protein can neutralize the virus, protect against symptomatic infection, and limit the progression of COVID-19.
The current study investigates a combination of two human long-acting neutralizing antibodies, AZD8895 (tixagevimab) and AZD1061 (cilgavimab), dubbed AZD7442. These were derived from the B cells of convalescent COVID-19 patients.
These molecules were developed from antibodies that showed potent neutralizing activity against the virus, with synergism between the two antibodies when present together. The antibodies were modified to increase the half-life while reducing the effector functions such as binding to the Fc gamma receptor (FcγR) and complement.
What did the study show?
The current study shows the results of the antibody cocktail on the prevention and treatment of SARS-CoV-2 infection in non-human primates (NHPs) and the pharmacological characteristics of this formulation in the healthy nasal mucosa of adult humans.
Both the antibodies individually showed high-affinity binding to the viral spike protein at different epitopes that were non-overlapping and located a fair distance apart on opposite facets of the RBD. The cocktail binds to the RBD at a 3,000-fold higher affinity than the ACE2 receptor, and either antibody powerfully blocked RBD binding.
When tested against the currently circulating variants of concern (VOCs) of the virus, the individual antibodies and the cocktail alike neutralized the viral particles with high potency at nanogram levels. The presence of binding at two different and distant epitopes ensured that the mutations present in the VOCs did not affect the neutralization activity of the drug.
The modified antibodies also extended the drug's half-life in NHPs, while reducing Fc effector functions in vitro. These functions include antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent complement deposition (ADCD), or antibody-dependent natural killer cell activation (ADNKA).
Thus, this drug is not associated with antibody-dependent enhancement of infection (ADE).
Moreover, the antibody cocktail effectively prevented and treated SARS-CoV-2 infections in NHPs, with viral subgenomic ribonucleic acid (sgRNA) undetectable in lung fluid samples from pre-treated animals after viral challenge. The dose used was only a fraction of that used in humans (4 mg/kg dose vs. 300 mg).
When the drug was given after viral challenge, the virus was cleared rapidly from the nasal cavity and the lungs within a week post-infection. Thus, the cocktail protects NHPs from infection and enhances viral clearance while reducing the level of inflammation within the lungs and preventing lung damage. It is likely to be useful in preventing and treating infection.
The neutralizing titers achieved in animals treated with AZD7442 were much higher than those seen in convalescent plasma. The Geometric mean neutralization titers (GMT) were 22-41-fold higher when given by intramuscular and intravenous routes, respectively, at seven days from the administration. Levels remained three-fold higher at nine months from administration, relative to convalescent plasma.
Especially important, high levels were seen in the nasal mucosa, an entry point for the virus. It appears that a single dose of AZD7442 can protect the individual for 12 months, at least.
What are the implications?
The researchers conclude, "AZD7442 demonstrated potent in vitro neutralization against SARS-CoV-2 VOCs, in vivo efficacy in both prevention and treatment settings of SARS-CoV-2 infection in NHPs, and extended half-life in NHPs and healthy adult participants."
Thus, it could protect vulnerable individuals after exposure, beginning almost immediately, or enhance immunity in those who do not respond adequately to vaccination. It is also likely to help those with weakened immunity.
Moreover, its ability to speed up viral clearance and prevent serious lung damage indicates its potential use as a therapeutic in COVID-19 patients to prevent serious disease. Further trials are planned, and their results will be eagerly awaited.
medRxiv 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.