Unpacking the Science Behind COVID-19 Vaccines

February 17, 2024

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Multiple safe and highly effective COVID-19 vaccines emerged in record time thanks to decades of critical foundational research combined with extraordinary global collaboration during 2020 between scientists, doctors, industry partners and government agencies.

Pioneering Scientists Behind Early mRNA Vaccine Technology

While the brisk pandemic vaccine timeline seemed sudden, the vital mRNA technology inside groundbreaking COVID-19 vaccines like Pfizer and Moderna traces back through fundamental biomedical discoveries in the 1960s and 70s.

Establishing Messenger RNA’s Essential Role as Molecular Messenger

  • Dr. Robert W. Holley’s research group at Cornell University first identified and isolated mRNA molecules in the late 1950s.
  • Their pioneering efforts mapping the structure and function of RNA helped earn Holley a Nobel Prize in 1968.
  • Holley’s work revealed mRNA’s essential role in protein synthesis – carrying coded instructions from DNA to cell machinery that assembles proteins.

Demonstrating How Proteins Are Assembled Using mRNA Templates

  • Building on Holley’s initial discoveries, Dr. Paul C. Zamecnik at Massachusetts General Hospital began investigating how proteins are made using mRNA templates in the early 1960s.
  • Zamecnik coined the phrase “message RNA” to describe this intermediary that translates genetic information into proteins.
  • By showing that ribosomes use mRNA to synthesize specific proteins, Zamecnik opened the door to manipulating protein production for medical uses – earning him a trip to Stockholm as well in 1978.

Early Concepts of Leveraging mRNA Therapeutically

  • These Nobel Prize milestones established messenger RNA as a pivotal molecular intermediary between DNA and functional proteins.
  • They revealed intriguing possibilities for utilizing synthetic mRNA to generate proteins in the body for therapeutic purposes.
  • This sparked concepts of mRNA vaccines and drugs decades before tools existed to produce modified mRNA stable enough for clinical testing.

Surmounting Key Challenges to Make mRNA Usable as a Vaccine Platform

But transforming mRNA into practical vaccines required overcoming substantial obstacles that stymied progress for 30 more years.

Preventing mRNA from Triggering Inflammatory Immune Responses

Efforts to leverage mRNA faced an elemental roadblock – mRNA injected into animals routinely triggered inflammation instead of the desired protein generation. The immune system attacked it as a foreign invader.

That instigating reaction stifled pharmaceutical mRNA applications until pioneering work at Pennsylvania’s Thomas Jefferson University in the 1990s upended assumptions.

  • Lead researcher Dr. Katalin Karikó hypothesized that substituting mRNA building blocks (nucleosides) would prevent immune recognition.
  • But early nucleoside modifications failed to sufficiently stop inflammation.
  • She persevered for years testing combinations until achieving improved mRNA translation without inflammation in breakthrough 2005 research.

Shielding Fragile mRNA Molecules for Cellular Delivery

Facing another key challenge, Vancouver-based scientist Dr. Pieter Cullis revealed lipid nanoparticles that envelop mRNA act as protective carriers transporting it into cells.

  • Synthetic lipid nanoparticles solve multiple problems – protecting fragile mRNA molecules, concentrating doses into particles and facilitating cellular uptake.
  • But years of formulation work remained converting raw mRNA into nanoparticles with drug-like properties suitable for pharmaceutical development before clinical testing.

Reaching an Inflection Point: The mRNA Vaccine Product Platform

As solutions to instability and delivery barriers clicked into place, the stage was set by 2010 to transform mRNA technology into actual vaccine candidates.

Visionary leaders at small biotechnology companies began collaborating with academic scientists to drive momentum.

  • BioNTech founders Dr. Ugur Sahin and Dr. Özlem Türeci collaborated with Dr. Karikó to evaluate early versions of its breakthrough mRNA vaccine platform.
  • Several key players later coalesced at UPenn including Dr. Weissman, an expert on viral immunology, who helped further optimize mRNA vaccine constructs.
  • The foundation now existed for rapid development when the coronavirus pandemic ignited an urgent need for new protective vaccines in 2020.

Rapid Development of COVID-19 Vaccines After Emergence of Novel Coronavirus

Catalyzed by decades of upstream mRNA research combined with revolutionary gene sequencing tools, multiple pharmaceutical companies and academic labs applied cutting-edge vaccine technology to combat COVID-19 following the novel virus’s identification in January 2020.

Emergence of Pfizer & BioNTech mRNA Vaccine

  • BioNTech leaders Dr. Sahin and Dr. Türeci scrutinized SARS-CoV-2 genetic data, recognizing its vaccine potential immediately.
  • By exploiting its mRNA platform, BioNTech rapidly developed vaccine candidates and began human trials by April 2020.
  • Fortuitous relationships with Pfizer – planning mRNA flu vaccines pre-COVID – transformed into partnerships enabling unprecedented global vaccine testing, approval, manufacturing and distribution.

Moderna mRNA Vaccine Pipeline Propelled by Earlier NIH Research

Modern developmental timelines proved nearly as swift by incorporating prior fundamental mRNA discoveries into rapid pandemic response.

  • Moderna benefitted from licensing earlier academic research on vital modified nucleoside mRNA patents.
  • Its platform relied heavily on fundamental techniques evolved by scientific pioneers like Dr. Karikó and Dr. Weissman at Penn and elsewhere under NIH support.
  • This work identifying and proving methods to stabilize mRNA and reduce innate immune responses fueled Moderna’s ability to advance vaccines at record pace.

Johnson & Johnson Single-Shot Viral Vector Vaccine

Alongside remarkable mRNA vaccines, viral vector vaccines like Johnson & Johnson’s generated immense life-saving impacts with differentiated benefits like single-dose protection.

Rather than mRNA instructions, J&J applied modified virus shells as delivery packages bringing DNA instructions into human cells to produce SARS-CoV-2’s distinctive spike protein:

  • Built on prior work on similar viral vector-based Ebola and Zika candidate vaccines
  • Led by Dr. Paul Stoffels, J&J orchestrated global teams to progress its vaccine in under 12 months
  • Combined its technology with worldwide partners to execute robust production of over 500 million COVID vaccine doses in 2021

Ingredients Within COVID-19 Vaccines

All approved COVID vaccines work by coaching your immune system to recognize some key sign of the novel coronavirus called SARS-CoV-2. But they incorporate slightly different sets of ingredients depending on the formulation to optimize safe efficacy.

mRNA Vaccine Ingredients – Pfizer and Moderna Examples

Though no COVID vaccines contain controversial elements like metals or fetal tissue, understanding contents like synthetic mRNA and protective lipids can help address safety questions.

PfizerModerna
mRNA Encoding Spike ProteinmRNA Encoding Spike Protein
2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide (ALC-0159)SM-102 (heptadecan-9-yl 8-((2-hydroxyethyl) (6-oxo-6-(undecyloxy) hexyl) amino) octanoate)
Distearoyl-sn-glycero-3-phosphocholine (DOPC)1,2-dimyristoyl-rac-glycero3-methoxypolyethylene glycol-2000 (PEG2000 DMG)
Cholesterol1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)
Monobasic Potassium PhosphateCholesterol
Potassium ChloridePotassium Chloride
Sodium ChlorideMonobasic Potassium Phosphate
SucroseSodium Chloride
WaterSucrose

No harmful preservatives or eggs/gelatin/latex compounds linked to allergic responses appear in mRNA COVID vaccines. But discuss any specific allergies with your doctor.

Viral Vector Vaccine Ingredients – Johnson & Johnson Example

The Janssen COVID vaccine similarly avoids concerning ingredients but uses a unique disabled adenovirus vector to supply DNA instructions, not mRNA.

  • Adenovirus type 26 (Ad26) viral vector disabled to not replicate in human cells
  • Citric acid monohydrate
  • Ethanol
  • Hydroxypropyl-β-cyclodextrin (HBCD)
  • Polysorbate 80
  • Sodium chloride
  • Sodium hydroxide
  • Trisodium citrate dihydrate
  • Water

COVID-19 Vaccine Development FAQs

Who originally conceived of vaccination practices and created the earliest vaccines?

While ancient Chinese and Indian cultures described inoculation procedures, the English physician Dr. Edward Jenner formally developed the first true smallpox vaccine in 1796 by expanding observations around cowpox conferring immunity against deadly smallpox.

Where are the highly efficacious Pfizer and Moderna mRNA vaccines actually manufactured?

Both pharmaceutical giants use complex decentralized global supply chains and centralized US finishing facilities. They mix raw materials at regional sites meeting strict quality guidelines while executing final vial filling and packaging steps domestically through hardened security and controls at specialized sites to ensure safety and availability.

How did bioengineer Katalin Karikó’s pivotal discovery make mRNA vaccines technologically feasible?

Dr. Karikó persevered testing mRNA building block combinations for years before finding specific modified nucleosides that prevented inflammatory immune reactions enabling cells to utilize external mRNA instructions successfully. This breakthrough discovery facilitated practical development of mRNA drugs and vaccines.

What strategic decisions and partnerships enabled Johnson & Johnson’s accelerated single-dose vaccine scale up?

J&J relied on preparatory work completed for other viral vector vaccines and simultaneous staging of clinical testing, approvals, and manufacturing by coordinating extensive global teams and contract partners. This intelligent parallel integration within constraints compressed an intrinsically complex 5-year timeline into just 11 months while delivering ~500 million doses in 2021.

Why was Kizzmekia Corbett recognized for special contributions to the Moderna mRNA vaccine?

An African American viral immunologist who headed an NIH research team that identified then characterized SARS-CoV-2’s spike protein, Corbett provided pivotal insights to Moderna confirming the spike antigen was sufficient to use in their rapid vaccine design without needing to incorporate other viral proteins as well.

Final Takeaways

  • Multiple vaccine formats safely trigger robust immune responses against SARS-CoV-2’s Spike protein.
  • Leveraged upstream mRNA breakthroughs to enable unprecedented compressed timelines.
  • Fruit of vast global cooperation from scientists to manufacturers to governments to healthcare workers.
  • Averted tens of millions of potential deaths while allowing recovery toward normal life.

Thanks to seminal basic research building an infrastructure to pivot accordingly paired with extraordinary collaboration fueled by crisis, safe and hugely effective COVID-19 vaccines emerged in record time. But behind abbreviated development stretch underappreciated stories of visionary scientists persisting through years of unseen labor to usher these lifesaving tools into existence just when humanity required them most.

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