November 19, 2020 § 2 Comments

Less than a week apart, two leading Covid-19 vaccines were announced as being more than 90% effective (Federal approval requires greater than just 50%).  These numbers auger well for broad scale combat of the virus.  Does this mean that a slew of other vaccines in development are also likely to emulate this success?  Not necessarily.  Depends on the approaches the others take. These two use a relatively new approach which took less than a year from when they began to the seeming end of a Phase 3 trial, albeit limited in size; unheard of speed in the firmament of vaccines.

Conventional vaccines introduce inactivated pathogens which trigger an immune response.  Being inactivated by heat or chemical means, they cannot cause the disease. But getting them to a safe while effective formulation takes time. The immune system retains the memory of this invasion (acquired immunity) and when a true disease pathogen is detected, activates the defense mechanism.  Acquired immunity is retained for some period. This is also the reason that acquiring the disease can provide immunity for years in many cases.  Edward Jenner, the English physician responsible for smallpox vaccination, is credited with coining the term vaccination, derived from the Latin vacca for cow and, vaccinia for cowpox. Famously, infection with the relatively benign cowpox conferred immunity from the deadly smallpox disease.

SARS COV-2, the virus creating the Covid-19 disease, was sequenced in early January 2020 by Chinese doctors.  This was made available worldwide.  The virus is about 120 nano meters in size and has an external lipid layer.  Thrusting through the lipid layer are spikes, known as the spike protein (see image). 

SARS-CoV-2 transmission electron microscopy image, courtesy NIAID-RML

This protein was an obvious target for the vaccine.  In a conventional vaccine it would be only one of many proteins eliciting antibodies.  To focus on just the spike protein, investigators turned to a messenger RNA (mRNA) approach.  As the name implies, mRNA conveys the genetic message to the cell to direct synthesis of a specific protein.  This specificity likely minimizes the possibility of side effects.

Here is how mRNA-based vaccines work.   Investigators devised an mRNA strand which could reliably direct the production of the spike protein when injected into a cell. This protein is known as an antigen.  The antigen will collect on the periphery of the cell, referred to as the antigen-presenting cell.  The antigens on the cell elicit an immune response (primary response) from the body. This activates cells which acquire a memory for this detection and response in what are known as memory cells.  When the person is infected with the SARS COV-2 virus, and the pathogen presents, the memory cells cause the immune response to kill the virus.

Instability of the mRNA strand is a concern at many stages in the process.  It will not survive long in the body, so ensuring cell entry requires that it be encapsulated in some way.  The most common means is a lipid (essentially fat) capsule.  Entry into the cell is facilitated and the lipid capsule preserves it for the duration prior to that.  Once in the cell, the mRNA strand directs the production of the antigen and then degrades and is no longer a factor in the body.

In lab settings, mRNA not tailored to be more stable requires storage at -70 C.  Most laboratories employing these methods have such freezers available.  When the mRNA needs to be used for experiments, it is often temporarily stored on the bench top in containers with liquid nitrogen or even dry ice (solid CO2).  But long-distance transport is still an issue, especially in low- and middle-income countries (LMICs).  Thus, distribution to LMICs is more complicated than simply the cost of the vaccine.  These countries are best served by vaccines that are stable at closer to ambient temperature.  mRNA can be designed to more thermally stable, especially through improved encapsulation.  Currently, we know that the Pfizer/BioNTech vaccine requires the conventional -70 C for storage.  The Moderna vaccine is stated to be stable at -20 C, and for some duration at refrigerator temperatures up to +5 C.

 A dark horse that I have not seen discussed in the press is CureVac, a German firm (as is BioNTech) in Tübingen.  It is expected to commence Phase 3 trials at the end of this year, whereas the other two are already seeking emergency approval.  What makes CureVac distinctive is that their emphasis has always been on thermal stability.  This characteristic is what triggered a (pre Covid-19) USD 52 million investment in 2015 from the Bill and Melinda Gates Foundation, which is known to be particularly interested in health solutions for LMICs.  In fact, the investment agreement requires low cost availability of vaccines in LMICs. CureVac claims 3-month stability at +5 C and 24 hours at room temperature.  The tortoise could overtake the hares, at least in LMICs.

Break on through from “Break on Through (to the other side)”, written and performed by The Doors (1967).

Vikram Rao

November 19, 2020


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