Mpox shows need for new approaches to therapeutic antibody research

Mpox – formerly known as monkeypox – is rapidly spreading in several African countries, prompting the World Health Organization (WHO) to declare a public health emergency. Stefano Gullà, chief scientific officer at Kling Biotherapeutics, discusses how new approaches in antibody research technology could halt this and other outbreaks.

Mpox is spreading rapidly in African countries, with the virus reported in 13 states, with over 3,000 confirmed cases and over 500 deaths reported, according to Africa Centers for Disease Control figures that were published in August 2024. Worryingly, there have also been cases that have spread to other continents, with a new version of the virus that has seemingly spread through contact between humans, including through intercourse.

Clade Ib is the virus type causing the most concerns at present, as previous iterations had only caused infections when a person came into contact with wild animals. It’s a different strain from the outbreak that occurred in 2022 – that was caused by clade II, which was less severe.

According to the latest information from the US Centers for Disease Control and Prevention (CDC), historical data suggests up to 10% of people die after infections with clade I, although recent outbreaks have seen death rates of between 1%-3.3%. More than 99.9% of people with clade II survive, according to the CDC.¹

Just as health experts are concerned about the spread of the disease, there are also worries about the pace of response from the life science industry. The first dose of mpox vaccines arrived in the Democratic Republic of the Congo (DRC) in early September - several weeks after the Africa CDC declared mpox as a public health emergency of continental security.

But the 100,000 doses of vaccine provided by Bavarian Nordic is not yet approved for children, who make up most of the cases. Officials have warned that a million more doses will be needed to get the outbreak under control. The available vaccines are also designed against the related virus that causes smallpox and there are uncertainties about whether this and the other available vaccine, made by Japan’s KM Biologics, will be effective against the clade Ib virus that is of high concern. Testing of the vaccine against the latest variant is happening in the field, with a trial of Bavarian Nordic’s vaccine Jynneos about to take place in DRC.

Several million more doses are on their way, with the US, European Union, and Bavarian Nordic, which are offering a few hundred thousand doses. Japan is also offering 3.5 million doses of KM Biologics’ LC16m8, which requires only one shot instead of two.
The Africa CDC, based in Addis Ababa, Ethiopia has estimated that 10 million doses are needed to rein in the outbreak, however, there are fears that this reaction has been too slow and that vaccines should have been made available when clade Ib was identified in September 2023.

Vaccines are the most potent tool we have to control and mitigate pandemic outbreaks, but they have inherent limitations: 1) vaccines work best in prophylactic setting by priming the immune system to mount a faster stronger response, there is little value for vaccines in a treatment setting. 2) Protective immunity may take weeks and multiple doses to fully establish resulting potential exposure and burden on the health care system. 3) Vaccines are less effective on the most vulnerable individuals, such as immunocompromised, elderly, and infants. And 4) in order to have an impact on pandemic spread, vaccines must be adopted by a large majority of the healthy population; this requires large safety studies, massive infrastructure, and coordination between public-private organisations.

New approaches

As we saw with the previous mpox outbreak and the COVID pandemic, there is a need to rapidly respond to the current outbreak, identifying a countermeasure and scaling it up so that there are enough doses to contain it.

An effective vaccine works by eliciting an immune response against the antigen, and in practice this means the production of antibodies that neutralize the viral infection. Some vaccines fail because the immune response is not strong enough or the antibodies produced are directed against the wrong antigen and therefore do not efficiently neutralise the virus. Rather than developing an entire new vaccine from scratch, one way to contain infectious diseases caused by viruses is to use the monoclonal antibodies directly.

These can be developed as a prophylactic drug, which can be injected into patients and would neutralise the virus should patients become exposed. Importantly, antibodies could also be used to counter infections in people already exposed.

There are some clear advantages to using antibodies – once identified, it’s easy to scale up production of monoclonal antibodies with the technology developed for other drugs over the past few decades. Furthermore, antibody therapeutics have been around for many decades, providing well established and predictable pharmacology.

We had a proof of concept (POC) COVID candidate during the COVID pandemic, when antibody drugs became part of the response to the virus, either as a prophylactic measure or as an alternative therapy to antiviral drugs once people become infected. For instance, GSK’s Xevudy (sotrovimab) is offered as an alternative to antiviral drugs as a way of preventing reinfection for up to four weeks.

Of course, identifying a candidate is crucial to the response to any emerging viral threat. In the case of COVID, the spike protein was identified early in the pandemic, allowing for vaccines and medicines to be developed rapidly. But keeping pace with emerging variants is still an issue with COVID, and the same will likely be true of any new viral threat. It’s vital to find strategies for rapid isolation of potent neutralising antibodies that can be used against any new strains.

In the case of mpox, this could be used to develop neutralising antibodies against emerging clades at speed. Research published by the US National Institutes of Health in COVID showed in 2022 that this approach was able to isolate an antibody known as SAR03, with both high binding neutralising activity.³ As the paper points out, there are several ways to generate antibodies for therapeutics research.

Traditional methods for identifying therapeutic antibodies are not suitable for the fast response required to combat emerging pandemics. The hybridoma method takes around six to eight months to generate leads, while potentially faster phage display is expensive and requires knowledge of the specific antigen to be targeted, and this is not always available for new emerging treats.

The emergence of single B cell technologies has accelerated timelines for identification and further development of antibodies for HIV, Ebola, and influenza in recent years. Importantly, by accessing directly human B-cells, it is possible to identify neutralising antibodies without extensive knowledge of the target antigen and thereby quickly respond to new threats (e.g., Disease X).

An important advancement is our ability to efficiently immortalise primary B-cells to retain the fully diversity of the immune response, while being able to culture the B-cells with standard procedures. This allows for the isolation of therapeutic antibodies from rare B-cell clones, and accelerated functional screening and selection of antigen-specific B-cell clones. The resulting cells produce fully human antibodies, as opposed to the chimeric or humanised antibodies produced by the alternative methods.⁴

Multiple disciplines need to come together to meet the stringent demand of pandemic response. B-cell immortalisation, high-throughput functional screening, and next generation sequencing offer a path to quickly discover highly effective neutralising antibodies. We can also control other aspects of the antibodies, such as effector function and half-life to optimise pharmacology, efficacy, and safety. A successful example of these technologies coming together is Sanofi and AstraZeneca’s Beyfortus (nirsevimab-alip), an anti-RSV monoclonal antibody approved for the prevention of RSV in infants. Beyfortus was discovered from immortalized human B-cells with a functional screen and further optimised with mutations enabling a long-acting effect.

I’m confident that today we have the technology to quickly respond to emerging pandemic threats to bring lifesaving antibody drugs to patients – it’s only a matter of time before a new disease threat emerges that requires global action.