How COVID-19 drug developers can stay ahead of viral variants
Identifying vulnerabilities and informing COVID-19 countermeasure design with genomic surveillance and in vitro tools
By combining genomic surveillance and in vitro tools, COVID-19 countermeasure developers can identify vulnerabilities to variants and design around them.
With a combination of genomic surveillance and in vitro laboratory assays, COVID-19 drug developers have the tools to get an early read on the vulnerability of their candidates to viral variants and course correct if necessary.
To date, no COVID-19 vaccine has proven variant-proof and some mAbs are impotent against certain variants. But not all therapies have exhibited reduced efficacy, and some companies think their countermeasures could avoid the issue due to features such as highly conserved drug targets that confer protection across a broad spectrum of viruses.
Because not all variants have the same effect and not all interventions are equally vulnerable, tracking the rise of variants and testing products again them as quickly as possible is crucial.
Companies don’t have to be blindsided by emerging variants, nor do they have to wait to find out how their molecules will perform against them. Rising prevalences and mutation patterns can provide early real-world hints of coming viral escape routes from authorized vaccines and therapies, and laboratory assays that apply selective pressure or mutagenesis can be used study the consequences of viral mutations and guide drug design away from vulnerable target sites.
For companies with early stage programs, the goal is to create therapies that are resilient to as many variants as possible. Companies with marketed products need to make decisions about when and how to develop next-generation versions.
In the latter case, the decision to ramp up new candidates will need to be weighed against diverting manufacturing capacity from vaccines or therapies that are effective against older and currently more prevalent variants.
FDA guidance expected in the coming weeks should help drug developers make these choices by outlining when updated versions of approved vaccines and therapies are needed and streamlining trial requirements for authorizations.
Acting FDA Commissioner Janet Woodcock said during a briefing Thursday that the need for product updates will hinge on two factors: the prevalence of the concerning variants, and the degree to which they compromise the original product’s efficacy. She did not specify a threshold for either parameter.
Mutations that confer resistance to mAbs or vaccine-induced immune responses should be predictable based on the increasing prevalence of certain variants, their mutation patterns in sequencing data and the use of in vitro assays to assess the functional consequences those of other mutations.
Resistance induced by antimicrobial compounds, for example, is typically gauged by culturing pathogens in vitro under drug pressure and sequencing the microbes that survive.
A study, published as a preprint in bioRxiv in January, showed a similar strategy could be applied to assess the potential rise of escape mutations to vaccines and anti-COVID mAbs. The paper, published again Wednesday in peer-reviewed form in Nature, reported the emergence of the spike mutations E484K, N501Y, K417N/T and L452 R in pseudoviruses cultured in the presence of mAbs isolated from vaccinated people — all of those mutations have been found in at least one emerging variant.
Antibody developers can also conduct site-directed mutagenesis or saturation mutagenesis assays to map the residues viruses could change to avoid antibody binding without losing the ability to bind their host receptor ACE2.
This work can be done early in product development to design candidates aimed at being effective against a wide array of variants.
Tillman Gerngross, CEO and co-founder of Adimab LLC spinout Adagio Therapeutics Inc., told BioCentury the company’s use of saturation mutagenesis revealed its mAb ADG20, slated to begin human testing this month, has only one vulnerability, a risk that is present in all betacoronaviruses but has not yet manifested in nature.
Companies with products already on the market may want to monitor emerging variants and design a next-generation vaccine or therapy that addresses the most important ones.
Genomic surveillance is crucial for tracking emerging variants that drug developers may need to prioritize; it has a second benefit of producing sequencing data that can be mined for patterns that point to specific mutations that make the virus more vulnerable or resilient.
A Feb. 3 paper in Science, first published as a preprint in November, demonstrated how detection of recurrent substitutions and deletions could zero in on escape mutations before they’re recognized in emerging variants.
Getting to next-gen products
Once problematic mutations that seem to be gaining a foothold are flagged, developers of authorized therapies can run assays to determine to what degree the mutations compromise their products, and start work on next-generation versions.
For these companies, deciding on the criteria for moving ahead with a next-gen product poses challenges.
AbCellera Biologics Inc. (NASDAQ:ABCL) CEO Carl Hansen told BioCentury that decisions to ramp up variant-directed programs shouldn’t be made lightly because switching to new candidates comes at the cost of “sacrificing some supply of the old antibody while you boot the next one up.”
AbCellera and partner and Eli Lilly and Co. (NYSE:LLY) have already needed to weigh this choice because bamlanivimab, which has emergency use authorization, can’t neutralize the B.1.351 variant that originated in South Africa. The mutant can also escape etesevimab, a mAb discovered by Shanghai Junshi Biosciences Co. Ltd. (HKEX:1877; Shanghai:688180) that Lilly is pairing with bamlanivimab. FDA granted an EUA for the combination Tuesday.
Hansen pointed to global prevalence of the variant and breadth of coverage as factors. He said that while the mAbs are effective in over 99% of COVID-19 cases, Lilly and AbCellera’s decision to advance a new neutralizing mAb was made easier by the identification of a candidate that can neutralize the original SARS-CoV-2 and all the current variants, not just B.1.351.
Developers of first-generation COVID vaccines have also started work on new versions to address variants. For example, Moderna Inc. (NASDAQ:MRNA) is developing a vaccine that could be given as a booster to extend immunity to variants, and CureVac N.V. (NASDAQ:CVAC), whose lead candidate is in Phase II/III testing, has started work on multivalent vaccines.
Novavax Inc. (NASDAQ:NVAX) told BioCentury via email that getting ahead of mutations will be more difficult for certain vaccine formats such as inactivated viruses and vaccines, including the company’s NVS-CoV2373, that deliver the whole spike. The company said because there are so many mutation combinations in the virus, with some SARS-CoV-2 variants possessing 17 mutations compared with the ancestral sequence, “it may not be feasible to be preemptively design constructs to what may appear.”
For these vaccines, companies may need to wait until variants are prevalent before developing new versions. Development of inactivated SARS-CoV-2 vaccines, for example, requires pathogen culture.
Adagio’s Gerngross disagrees that developers of spike-directed candidates need to wait for variants to emerge. He thinks it’s possible to design spike vaccines that aren’t vulnerable to variants.
Instead of delivering near-recapitulations of the spike, the way to bypass SARS-CoV-2’s propensity for escape mutations is to “present the antigen in a way that you will get antibodies" that are broadly neutralizing against highly conserved epitopes. The company is working on how to use broadly neutralizing antibodies to inform the design of such a vaccine.
Inducing strong T cell immune responses, which are peptide-based, is another strategy for creating more resilient vaccines. Mutations that change an antigen’s structure and render an antibody ineffective may not prevent a T cell attack; and the combination of viral sequencing data with technologies to predict T cell epitopes could enable the design of vaccines targeting highly conserved sequences within and outside the spike.
There are at least eight COVID-19 vaccine programs designed to induce T cell immunity, with two in the clinic: AV-COVID-19 from Aivita Biomedical Inc. and LV-SMENP-DC from Shenzhen Geno-Immune Medical Institute..
Therapeutic risk reduction
Therapeutics companies are taking two main approaches to mitigating the risk of escape or resistance variants: creating products against multiple targets or against a target site that is highly conserved because it’s required for function.
Regeneron Pharmaceuticals Inc. (NASDAQ:REGN) was an early adopter of the multitarget approach and developed a mAb cocktail with the philosophy that multiple antibodies will be harder to escape than one. FDA granted its casirivimab/imdevimab an EUA in November.
Vir Biotechnology Inc. (NASDAQ:VIR) was an early proponent of the conservation strategy and set out to target epitopes shared between SARS-CoV-1 and SARS-CoV-2. Vir’s VIR-7831, which was engineered to have a high barrier to resistance, is in Phase III testing.
Both strategies are panning out. VIR-7831’s parent mAb is only slightly less potent against the B.1.1.7 variant first identified in the U.K., and unaffected by B.1.351. Regeneron’s cocktail seems largely unaffected by both variants — even though one of the mAbs, casirivimab, is about 59-fold less potent against B.1.351, the other antibody, imdevimab, can still potently neutralize both variants.
Molecular Partners AG (SIX:MOLN) is incorporating both the conservation and the multitarget approaches. Two of its COVID-19 DARPin candidates target the spike’s receptor-binding domain, and both DARPins have three binding sites, which CEO Patrick Amstutz told BioCentury offers “more of a dynamic range. Even if some start to lose binding, they’re still helping.”
Adagio has extended the epitope conservation idea to include pre-emergent coronaviruses species that are circulating in animals but not yet in humans, and can invade cells in culture via human ACE2 or animal ACE2 orthologs. Gerngross told BioCentury that ADG20, which was derived from a mAb isolated from a SARS-CoV-1 survivor, was optimized both for SARS-CoV-2 neutralization and for potent activity against SARS-CoV-1 and other coronaviruses.
Gerngross said the goal is not only to avoid SARS-CoV-2 escape mutants but, given zoonotic reservoirs of potential human pathogens, to also have a broadly neutralizing mAb ready for the next coronavirus outbreak.
Small molecule polymerase inhibitors show the conservation approach has legs. RdRP is one of the most conserved RNA virus genes, and three of the leading RdRP inhibitors for COVID-19, including the approved therapy Veklury remdesivir Gilead Sciences Inc. (NASDAQ:GILD), were repurposed from non-coronavirus indications.
A Gilead spokesperson told BioCentury the mutations in B.1.1.7 and B.1.351 don’t significantly alter RdRP or “have any association with known mutations conferring reduced susceptibility of coronaviruses to remdesivir in vitro.”
Atea Pharmaceuticals Inc. (NASDAQ:AVIR) founder, Chairman and CEO Jean-Pierre Sommadossi added that no significant SARS-CoV-2 mutation that preserves RdRP function and lowers nucleoside analog potency has ever been detected. Atea’s candidate, AT-527, is in Phase II testing.
Sommadossi said a way to guard against the low risk of RdRP resistance mutations is to discover different scaffolds with different mechanisms because it’s unlikely viruses will develop cross-resistance to all the candidates.
Veklury and Phase II/III candidate molnupiravir from Merck & Co. Inc. (NYSE:MRK) and Ridgeback Biotherapeutics L.P. have been shown to have different sensitivities to RdRP mutations; and Sommadossi said AT-527 has a different mechanism than the other two compounds.
ACE2 – Angiotensin-converting enzyme 2
SARS-CoV-2 RdRP (SARS-CoV-2 nsp12) – SARS-CoV-2 RNA-dependent RNA polymerase