Could horse-derived antibody therapy be effective against SARS-CoV-2 variants of concern?
A new study, released as a preprint on the bioRxiv* server, reveals the high neutralizing efficacy of hyperimmune horse serum against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This could prove, if validated, to be a more affordable yet potent therapeutic in reducing the morbidity and mortality caused by this virus. The current pandemic of coronavirus disease 2019 (COVID-19) has already killed over 3.84 million people the world over while putting enormous strain on social and financial wellbeing. In order to prevent and treat the disease, a range of antivirals, antibodies and vaccines have been explored. Intensive funding and research led to the rollout of the first vaccines within a year after the pandemic was first declared. Vaccines  Several different vaccines have been developed, based on messenger ribonucleic acid (mRNA), protein subunit, virus vector and inactivated whole virus platforms. Many of these have shown high efficacy in reducing the rates of severe symptomatic illness. However, they are demanding in terms of manufacture and distribution. As a result, low-income and developing countries lag in vaccine coverage. A second issue is the emergence of newer variants. Many of these, such as the alpha (B.1.1.7/501Y.V1), beta (B.1.351/501Y.V2) and epsilon (P.1) strains, have shown higher transmissibility, or the ability to escape antibody recognition by therapeutic mAbs, or antibodies in CP, or serum from vaccine recipients. Convalescent plasma  Convalescent plasma (CP), also known as hyperimmune serum, is obtained by pooling serum from many donors who have recovered from the infection. Previously used in the treatment of influenza and Ebola virus infections, it still requires a mean expenditure of up to 1,000 USD per treatment. It also requires a lot of laboratory expertise and facilities for ruling out the presence of blood-borne pathogens and ensuring that specific neutralizing antibodies to SARS-CoV-2 are present in the donor serum. This may be in short supply in resource-limited countries. Moreover, it is dependent on the supply of donors. Monoclonal antibodies  Monoclonal antibodies (mAbs) have been projected as safe and effective alternatives to clear the virus but are even more costly at up to 6,500 USD per treatment. Manufacturing costs are high and require sophisticated facilities. Instead, equine polyclonal antibodies may be used as such or only the required fragments. These have a long history of use against venoms and viruses. This could prove an invaluable asset in the present situation, as laboratories that manufacture these agents are already operating in a host of countries. This could help supply these antibodies all over the world to provide safe treatment for SARS-CoV-2 in a cost-effective manner, saving hundreds of thousands of lives. The advantage of using equine antibodies is that horses can be immunized with ease against SARS-CoV-2 antigens, yielding polyclonal antibodies (pAbs) in large amounts. This serum neutralizes the virus 50-80 times more efficiently than CP from human donors. While these findings have led to clinical trials establishing the safety of pAb F(ab)2 fragments (antibody-binding fragments) against moderate to severe COVID-19 and testing its efficacy in such cases, there is little evidence that they are effective against variants of concern (VOCs) of SARS-CoV-2. Powerful neutralization efficacy  In the current study, the researchers found that equine pAb formulations raised against recombinant SARS-CoV-2 spike S1 subunit, or against the so-called SEM mosaic (spike, envelope and mosaic antigens) in a recombinant protein, were able to neutralize four VOCs  the alpha, beta, epsilon and gamma (B.1.427/B.1.429) lineages. In all cases, they did so at similar low concentrations, indicating high neutralization efficacy. In fact, compared to the pAb concentrations used to treat patients in other trials, at 4 mg/kg, the half-maximal inhibitory concentrations (IC50) for these formulations were a thousand-fold lower, ranging from 0.146 g/mL to 0.377 g/mL. The highest IC50 was 13.89 g/mL for the beta VOC. The pAbs showed themselves able to neutralize both the parental SARS-CoV-2 and the VOCs with comparable potency, further heightening their potential for COVID-19 therapeutic use. While the circulating VOCs have demonstrated their resistance to antibodies elicited by first-generation vaccines and to therapeutic mAbs, the current study shows that hyperimmune horse serum contains polyclonal antibodies that possess high neutralization efficacy against four VOCs. This indicates that, in view of their safety, effectiveness, and the broad availability of manufacturing facilities, equine pAbs represent a potentially low-cost and easily scalable approach to COVID-19 treatment. The researchers write:  Our data suggest high potential of equine pAbs for treatment of COVID-19. By shifting antivenom platforms to produce equine pAbs, laboratories in both developed and developing countries that have been manufacturing and distributing safe and standardized antivenoms for decades could rapidly fill the gaps in global demand for therapies that are both effective against VoC and affordable to low- and middle-income countries.  *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.