By Guillaume Trusz and Brian Zabel

Over the last couple of months, practically every biopharmaceutical company has committed itself to fighting COVID-19 in one form or another. That being said, not everyone can play in the big leagues. The top three biopharmaceutical companies of the US, both in terms of revenue and market capitalization, include Pfizer, Merck, as well as Johnson and Johnson (not necessarily in that order) and each have carried about this pandemic in very distinct ways. On the other side of the Atlantic, GlaxoSmithKlein and AstraZeneca have put up formidable vaccine platforms as well. With a burgeoning number of therapeutics and vaccines concretizing it is only a matter of time until we find out who the real winners are…

Pfizer & BioNTech – BNT162b1 & BNT162b2 – liposome-based mRNA vaccines – Phase 2/3 Ongoing

Pfizer still rides the wave of its successful Eliquis® (apixaban) anticoagulant drug and eagerly awaits the completion of Viatris, the resulting company from the merger between Upjohn, Pfizer’s off-patent drug unit, and Mylan, a global generic manufacturer. So, Pfizer’s cash continues to flow like cold beer on a hot Texas Tuesday…

Early in the pandemic, Pfizer partnered with BioNTech, a German biotechnology company. Prior to the initiation of the collaboration, BioNTech had initiated Project “Lichtgeschwindigkeit” or “LightSpeed” which spanned from lead candidate identification to GMP manufacturing of their novel vaccine. Both BNT162b1 and BNT162b2 are liposome-based mRNA vaccines: BNT162b1, contains mRNA encoding the SARS-CoV-2 receptor binding domain (RBD), and BNT162b2, mRNA which encodes the full-length spike protein. Cells that become transfected by the liposome are expected to express the protein encoded by the carried mRNA. The protein will eventually be translated in the cell cytoplasm and expressed on the outer surface of the cells, where it will be recognized by the host’s immune system to stimulate protective B- and T-cell responses.

Under Operation Warp Speed, the US government has secured 100 million doses of the BNT162b1 vaccine, pending Food and Drug Administration (FDA) approval. However, concerns of ultra-low temperatures when it comes to the storage and distribution of the said vaccine have clouded recent advances. More traditional protein subunit vaccines are much more stable and can be kept at room temperature for extended periods of time. Administration of Pfizer’s vaccine in conventional office or pharmacy settings could complicate matters further when it comes to the global clinical supply chain.

Although their idea is awfully close to Moderna’s, Pfizer has one advantage in that name recognition will play a major role in their product’s global marketability. So luckily for Pfizer, it will no longer need Jake Gyllenhaal to sell its product…

Merck (MSD) – vesicular stomatitis virus (VSV) & measles virus-based vaccines – Phase 1/2 Ongoing

Despite being well positioned to tackle this pandemic, as it continues to pursue various vaccines for intractable diseases such as Ebola and HIV, Merck has carried about the last couple of months in a comparatively subtle manner.

Merck has been working on a vaccine that uses an engineered vesicular stomatitis virus (VSV), a virus that commonly infects horses and cattle and manifests itself with similar symptoms as foot-and-mouth disease. The vaccine’s active ingredient consists of a live VSV, and its surface has been modified to express the spike protein of SARS-CoV-2. Thanks in part to the modern merits of genetic engineering, although the weakened virus can still replicate, it cannot cause disease. In late 2019, Merck received marketing authorization from the FDA for Ervebo® (a Zaire ebolavirus vaccine) that uses the same VSV construct and has proven quite effective in several African nations.

Another lead product includes the use of an attenuated measles virus that also expresses the spike gene of SARS-CoV-2. V591, which operates under a similar mechanism of action as the VSV vaccine, was obtained by Merck during its recent acquisition of Themis, an Austrian vaccine company, and has begun its Phase 1/2 trial in Belgium earlier this month.

Merck’s CEO, Kenneth Frazier, has disclosed that numerous obstacles stand in the way of anyone achieving a marketable product by years’ end. Merck, which currently still holds the record for the fastest approved vaccine, Mumpsvax® for the mumps virus, could be quickly dethroned. Nevertheless, Frazier does bring up valid concerns. Research and development performed at backbreaking speeds could ultimately crash and burn and an approval prior to the full completion of the set clinical trials could engender controversy. An entire field known as pharmacovigilance is dedicated to the study of side effects from biopharmaceuticals following their approval. Various medicinal products have received everything from a Black Box Warning to a loss of marketing authorization following the announcement of various severe adverse effects, despite most of those products not having been developed in an expedited manner.

The tortoise and the hare is a tale as old as time itself, but Merck’s strategy could prove detrimental if the speedier vaccines turn out to be a success (both in safety and efficacy), and participant recruitment will become ever so complex in terms of treatment-naïve populations once other biotechnology companies finally reach the clinical trial stage.

Johnson and Johnson (J&J) – Ad26.COV2.S – adenovirus-based vaccine – Phase 3 Ongoing

For certain vaccines, the first dose does not always provide the best and most robust immune response possible and thus a second or even multiple doses are required. This poses issues both from a logistic and practical point of view (i.e. having patients not return to medical centers for the needed follow-up doses as well as patients having a false sense of immunity following the initial injection). As a result, J&J has come out with a single dose vaccine.

J&J’s investigational vaccine is based on adenovirus serotype 26 (Ad26) and expresses a stabilized spike protein. Recent pre-clinical results in non-human primates proved successful in the development of neutralizing antibody titer, and although scientists have concluded that a second Ad26.COV2.S vaccine dose could further improve the already decent results, J&J stands with its one dose policy, possibly playing into the psychology of patients. Trypanophobia, or the fear of needles, consistently ranks high when it comes to people’s everyday fears, although not as high as arachnophobia (fear of spiders) and glossophobia (fear of public speaking), with the latter ironically ranking higher than thanatophobia or fear of death itself.

With inhaled influenza vaccines becoming quite common, numerous other companies, such as Vaxart and Altimmune, have explored the route of intranasal or inhalable COVID-19 vaccines. But other issues could surface in terms of differences in tidal volumes based on age and gender, as well as loss of vaccine product when exhaling following the initial inhalation. The success of the inhalable vaccine for influenza, such as FluMist®, is clearly beneficial when considering annual dosing, as well as the potential for inhalable insulin which requires a consistent and recurring daily dosing (sorry Nektar…) but a clear benefit in aerosol COVID vaccines remains to be seen, especially as efficacy outweighs convenience.


GlaxoSmithKlein (GSK) & Clover Biopharmaceuticals – SCB-2019 – recombinant subunit vaccine – Phase 1 Ongoing

GSK is built on strong bones, literally. Glaxo Laboratories, which was based out of Wellington, New Zealand, started out selling milk formula-based products for babies. Over the years, through various acquisitions and mergers, GSK has infiltrated several markets from toothpastes to numerous over the counter (OTC) medicines, making them almost as multi-faceted as J&J.

GSK has partnered with Clover Biopharmaceuticals, a biotech company in Chengdu, China. Clover’s COVID-19 S-Trimer vaccine, which mimics the native trimeric SARS-CoV-2 spike protein, has had success in developing significant neutralizing antibody levels in multiple pre-clinical studies. GSK offers its well-developed squalene based AS03 adjuvant which has undergone numerous clinical trials for various influenza A vaccines such as hemagglutinin (H) 1 and neuraminidase (N) 1, or H1N1 for short, H5N1, and H7N9. Often referred to as an immunologist’s “dirty little secret”, finding the right adjuvant for a vaccine is key as it not only improves the duration but also the quality of the recipient’s immune response by stimulating it at various levels. Well known vaccine adjuvants include thimerosal (a mercury salt which is no longer in use) and the much more common aluminum hydroxide. Moreover, adjuvants play a key role in pandemic situations as their incorporation in the final vaccine product can decrease the amount of protein needed per dose, ultimately translating to more vaccine doses being available in a shorter amount of time.

More recently, GSK has also partnered on another recombinant protein-based vaccine with Sanofi, conveniently funded by the US government’s Operation Warp Speed. DNA encoding the SARS-CoV-2 spike protein is inserted into a plasmid and using baculovirus particles transported to proprietary mammalian host cells that are programmed to produce large quantities of the spike protein. This manufacturing process mimics Sanofi’s Flublok® Quadrivalent influenza vaccine which produces influenza hemagglutinin proteins and remains the only recombinant protein-based influenza vaccine approved by the FDA. Once purified, the spike proteins will be formulated with GSK’s AS03 adjuvant and later down the line administered to patients.

The big question is, will GSK be as successful in the US as it is poised to be in Europe, or will it need Mathew McConaughey to help smuggle its pre-approved vaccine just as he did with AZT?

AstraZeneca (AZ) – AZD1222 – adenovirus-based vaccine – Phase 3 Ongoing

Previously known as ChAdOx1 nCoV-19, AZD1222 uses the ChAdOx1 weakened adenovirus construct developed at the University of Oxford that has been engineered to express the SARS-CoV-2 spike protein. The use of weak virus strains to stimulate one’s immune system is one of the pillars of vaccinology. Using less virulent strains dates back to the late 1700’s when country doctor Edward Jenner used cowpox lesions from the hands of local dairymaids to inoculate (or in this case variolate) people so as to protect them if infected with the actual smallpox virus. Jenner’s experiment proved successful, and although he was not the first person to try such an approach, he is now hailed as the father of immunology and the word vaccine, which stems from the Latin vacca, for cow, is forever associated with Jenner’s fabled ruminants. AZD1222 should be relatively safe as it is replication-deficient and cannot propagate in a vaccinated patient or transmit from person-to-person, yet it should prove effective in stimulating a protective immune response against SARS-CoV-2.

Although both J&J and AZ’s vaccine platforms are both adenovirus-based, the AZD1222 vector potentially appears more attractive due to the fact that this adenovirus is chimpanzee derived (versus J&J’s which is human adenovirus derived). Because this virus is not as prevalent within the human population, this should ultimately mitigate the risk of individuals having preexisting neutralizing antibodies towards the viral particles which could be detrimental to the overall efficacy of the vaccine.

As the vaccine race heats up, Moderna, Pfizer and AZ lead the way with anticipated approval dates for each of their products set for Q4 of this year, with reports predicting AZ to be the first to have an approved vaccine product (although the Kremlin and Mother Russia would greatly refute this claim). However, this is not AZ’s first rodeo with Pfizer; we all remember the Statin Wars between Crestor® and Lipitor® as well as Pfizer’s attempted takeover of British-Swedish biopharmaceutical company in 2014, which at the time would have made Pfizer the largest biopharmaceutical drug company in the world… an AZ COVID-19 vaccine approval will simply add another notch on the belt.

The fight towards a successful vaccine will carry on for a little while longer (but hopefully not longer than the Cowboys have waited to make Dak Prescott a worthy offer). A single vaccine will surely not be the solution, in fact multiple vaccines stand to be approved, but as head-to-head comparisons still lack very few companies will come out of this pandemic unscathed.

Moreover, as the approval date of a vaccine quickly approaches it will be interesting to see which issues precipitate within the misguided anti-vax community. From expedited vaccine development, to possibly loosened FDA requirements, to a simple lack of trust in the biopharmaceutical industry, anything can happen.

Guillaume Trusz

Author Guillaume Trusz

Guillaume Trusz received his B.S. in Molecular, Cell, and Developmental Biology from the University of California, Los Angeles (UCLA) in 2015 and his M.S. in Biomedical Imaging from the University of California, San Francisco (UCSF) in 2018. Prior to working as an Associate Scientist in the Discovery Immunology Group at Curia, Guillaume contributed to various academic and industry related research projects pertaining to small molecules, nanoparticles, as well as biosimilars.

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