SARS-CoV-2: On the rise again?
For some, the COVID-19 pandemic might already seem a distant memory – a time of remote work, toilet paper hoarding, and questioning the reusability of face masks. However, as of mid-February 2025, SARS-CoV-2 activity has been increasing globally, with overall test positivity rates reaching 11% in May. This increase is, however, strongly region-dependent. While African, European, and American regions report low levels of the virus, more positive tests are observed in the Eastern Mediterranean, South-East Asian, and Western Pacific regions.
Despite these regional differences, a primary driver of the increase in patient numbers appears to be a decline in vaccination rates. The WHO reports that, on average, only 1.68% of older adults and 0.96% of healthcare workers received a vaccine dose in 2024, possibly leading to waning immunity in recent months. Generally, the uptake of booster vaccines, which target relevant variants, also appears to be poor. One such variant, NB.1.8.1, is likely contributing significantly to the rise in infections. This variant possesses spike protein mutations that lead to stronger binding to human ACE2 receptors, better uptake into human cells, and greater immune evasion. A very rapid increase in the circulation of this variant, with sequence prevalence jumping from 2.5% in March to 10.7% in April, likely contributes to the overall trends observed.
Preventing history from repeating itself
Due to the continuous emergence of novel SARS-CoV-2 variants, the risk of another outbreak reaching pandemic proportions within the next 10 years is substantial. To prevent a scenario similar to that which began in 2020, there is an urgent need for novel vaccines, innovative therapies, and robust preparedness strategies.
The current arsenal of drugs available to treat COVID-19 remains limited. The antivirals remdesivir (Veklury®) and molnupiravir (Lagevrio®) both target the RNA-dependent RNA polymerase, while nirmatrelvir/ritonavir (Paxlovid®) targets the main protease of the virus. Some of these drugs come with significant disadvantages, notably interactions with other medications. Ritonavir, for instance, is a potent inhibitor of the liver enzyme CYP3A4, which metabolizes many other drugs. Co-administration of this antiviral with commonly used therapeutics, such as statins or blood pressure medication, can lead to serious adverse effects and even death.
Furthermore, in a number of cases, the currently available drugs are contraindicated for certain patient populations, such as those with kidney or liver impairment, or pregnant/breastfeeding women. It is also crucial that these drugs are administered as early as possible in the course of infection, as their primary mechanism targets early viral replication. Lastly, resistance against some of these drugs has been reported in both in vitro and in vivo (clinical) settings.
Belgian breakthrough targeting viral assembly
Recently, two Belgian research groups have published their groundbreaking progress in the development of a novel anti-SARS-CoV-2 therapeutic in the prestigious journal Nature. Both groups independently identified a compound that acts on the viral M (membrane) protein. The M protein is the most abundant viral structural protein and is considered the major coordinator of viral assembly and membrane budding. Its ability to transition between short and long forms is essential for its function.
The research team from Johnson & Johnson Innovative Medicine recently identified a small-molecule inhibitor, JNJ-9676, that targets the M protein of SARS-CoV-2 and other sarbecoviruses. JNJ-9676 binds to the M protein, stabilizing it in an altered conformation, thereby preventing the release of infectious viral particles. Interestingly, the compound demonstrates activity not only in in vitro models but also in SARS-CoV-2 hamster models. Both prophylactic and therapeutic regimens showed the M-protein targeting molecule to be effective in reducing viral load.
On the very same day, the work of Professor Johan Neyts’ research team at KU Leuven was also published in Nature. These researchers identified a compound, CIM-834, effective against SARS-CoV-2, which also acts on the M protein. Cryo-electron microscopy revealed that CIM-834 similarly inhibits the conformational transitioning of the protein by locking it in its short form. Mouse and hamster models further confirmed its effectiveness in an in vivo setting.
The independent yet convergent findings from these Belgian research groups highlight the great potential of targeting the SARS-CoV-2 M protein to disrupt viral assembly. With promising preclinical data for JNJ-9676 and CIM-834, the journey towards clinical validation is a crucial next step, offering a powerful new strategy to bolster our defenses against not only current variants but also the emergence of future pandemic-level coronaviruses.
