Nebulized mRNA-encoded antibodies found to protect hamsters against COVID-19


The world has recently seen immense activity in the field of vaccine development due to the coronavirus disease 2019 (COVID-19) pandemic, as the causative virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to emerge in new variants with increased transmissibility, immune escape capability and virulence attributes.

The use of mRNA to encode vaccines in the form of SARS-CoV-2 spike protein was pioneered by the Pfizer/BioNTech and Moderna vaccines. These were among the many vaccine technologies pressed into use to counter the relentless spread and the rising death toll of the COVID-19 pandemic.

In addition, monoclonal antibodies were also isolated for their neutralizing activity against the virus, both pre-and post-exposure. Emergency use authorization (EUA) was obtained for four mAb protocols: the therapeutic mAbs casirivimab + imdevimab, bamlanivimab + etesevimab, and sotrovimab and the prophylactic mAbs tixagevimab + cilgavimab. Of these, the first two are no longer effective, and their EUA has been withdrawn.

These antibodies need to be given intravenously, necessitating a medical setting. They must be delivered in relatively large doses of 10–100 mg kg−1 to compensate for the fact that only a small fraction reaches the site of interest. This drives up the cost of treatment, limiting their availability, especially in low- and middle-income countries (LMIC).

Alternative methods of mAb production need to be explored. The current paper, published in Advanced Science, discusses such an alternative, where a formulation amenable to nebulization was designed to allow the introduction of antibody-encoding mRNA into the lungs to neutralize the disease. Both in vitro and in vivo results support the use of this novel technology to fight not only COVID-19 but also other respiratory virus infections.

The use of mRNA is safe in that it does not enter the nucleus, unlike DNA or viral vectors carrying DNA, which relies on their effect on nuclear entry and integration with the host DNA genome. Secondly, the half-life of mRNA in circulation is relatively short, avoiding long-term consequences. By reducing the required dose to a hundredth of the original amount, when delivered directly to the respiratory tract rather than systemically, the overall cost of therapy is significantly decreased.

Prior research showed that this approach was feasible, using intravenous lipid nanoparticle (LNP)-encapsulated mRNA encoding a neutralizing antibody against the chikungunya virus, which would be expressed in the liver.

Earlier research by the same authors showed the capability to direct mRNA to the lungs to produce mAbs there. By avoiding the need to introduce the recombinant spike protein, the researchers encoded a membrane anchor in the heavy chain of the immunoglobulin G (IgG) antibody molecule. This allowed the tissue to retain the antibody for several weeks.

The current study moved a step further by shifting from the earlier intratracheal administration to nebulization, which can be performed by the individual outside a medical setting. This would allow the mAbs to be expressed at high concentrations at the mucosal surface, the principal site of entry of respiratory viruses, while avoiding the need to administer large doses systemically.

Hamster model

Following these promising in vitro findings, further testing was carried out in Syrian golden hamsters, which provide a robust animal model for human COVID-19 infection.

Longer retention in lungs

This demonstrated that the antibodies were, as expected, anchored to the cell membrane in the lung by the GPI molecule. Compared with the secreted or non-anchored form, it was found to remain in the lung tissue. At the same time, the latter led to increased serum concentrations, the difference in post-transfection serum levels being 27-fold in favor of the secreted form. This occurred despite the efficient translation of both types in lung tissue following nebulization, peaking at 24-48 hours.

The encoded anchor enhanced lung retention from just over one day to seven days.