Whither mRNA Therapeutics Under the Current Regime and Beyond?

One of the more remarkable things I have ever seen has been the demonization of the middle component of the Central Dogma of Molecular Biology in the past four years.  The Central Dogma was formulated in late-1950s by Francis Crick, co-discoverer of the double helix structure of DNA with James D. Watson:  DNA makes RNA makes Protein, with the RNA in the middle being mRNA – messenger RNA.  The Central Dogma was and remains a triumph of modern molecular biology, albeit with minor modification to account for retroviruses in which RNA makes DNA makes RNA makes Protein.  Horace Freeland Judson covered this history for the general reader very well in The Eighth Day of Creation, 1996 (orig. 1979, and still relevant for students of modern biology).

But after some reflection it is not so difficult to understand how this one class of molecule has gotten its reputation.  President Trump v1.0 rightly viewed Operation Warp Speed as a major achievement of his initial term, during which the first COVID-19 vaccines were developed using mRNA as the platform to produce the spike protein in the vaccinated, thereby conferring immunity to SARS-CoV-2.  This was a considerable technical achievement, a public-private partnership that made a pandemic vaccine in record time.  Unfortunately, none of the COVID-19 vaccines has worked as the people have come to rightly expect of vaccines.  They prevented neither the disease nor its transmission, although they did moderate the course of disease in many patients and by doing so have accounted for millions of saved lives according to several analyses.

This relative failure was because neither previous infection nor vaccination against coronaviruses produces durable immunity to subsequent exposure to the virus.  Thus, the problems with the COVID-19 vaccines probably had very little to do with mRNA.  But the perception of mRNA vaccines has put a huge damper on prospects for RNA therapeutics in general, as outlined in this feature article in Nature (paywall) by Elie Dolgin from the 15 May 2025 issue.  This is unfortunate, because the prospects of mRNA-based therapeutics are strong for other diseases.  Much of the fallout can be ascribed to the current Administration consensus represented by Robert F. Kennedy, Jr., Secretary of Health and Human Services.  As is well known, despite his sporadic protestations to the contrary, RFKJr has been an incorrigible anti-vaxxer for a long time.  We can leave that discussion for another time and include his efforts to tackle chronic disease.

The COVID-10 scientist’s perspective can be summed up in “From Hero to Zero” in Dolgin’s article:

Five years ago, the US government was spending billions of dollars to support the development, manufacturing and roll-out of mRNA vaccines, which played a major part in curbing the COVID-19 pandemic.  Pharmaceutical companies were pouring in capital and building ambitious pipelines centered on mRNA.  The technology was feted with a Nobel prize. [1]  Investor confidence was sky-high… Now, in the span of just a few months, the mood across the industry has grown darker – chilled by a newly hostile political climate.

Many biotech leaders avoid speaking out in public but it is clear that a perfect storm has beclouded the future of mRNA therapeutics.  Apart from the generalized attack on American biomedical science it is clear that:

Much of the current antipathy towards mRNA vaccines can be traced back to the COVID-19 pandemic, and the political and cultural backlash it left in its wake.  Critics cite the compressed timelines and emergency use authorizations as signs that the safety of the vaccines was compromised. Vaccine mandates – imposed by governments, employers and schools – further fueled resentment.  Meanwhile, conspiracy theories about DNA alteration and population control continue to circulate widely online, deepening public mistrust and giving political traction to opposition against mRNA technology.

What began as fringe skepticism has increasingly entered the mainstream consciousness, amplified by partisan media and political figures who frame the vaccines not as public-health tools but as symbols of government overreach.  Among the most prominent of these is Kennedy, now secretary of the US Department of Health and Human Services (HHS), who has long questioned the safety of childhood immunizations and built his political brand on vaccine resistance. (HHS officials did not respond to requests for comment.  A spokesperson for the White House pointed to a public statement that did not address the questions posed by Nature.)

There is little to argue with here.  Most of those leading a movement against mRNA technology seem to be “individuals in the medical freedom movement…(who)…contend that COVID-19 vaccines were rushed through approval without adequate long-term testing, alleging that safety corners were cut in the name of speed, and that the risks of mRNA platforms continue to be deliberately downplayed.”

And in these contentions lie the current problems with prospective mRNA therapeutics that have been caused by the COVID-19 mRNA vaccines.  As I wrote years ago in a different context:

While the science that has led to these mRNA vaccines is not experimental, the patent experimental nature of both SARS-CoV-2 mRNA vaccines has not been discussed, very much, in public.  If either mRNA vaccine turns out to be ineffective or worse, harmful, the backlash will be severe.  After the rollout of the Salk polio vaccine in 1955, problems with manufacture led to several hundred cases of polio because a batch of killed virus was contaminated with live virus.  The response to that mostly localized catastrophe was rapid.  The production error was identified and corrected immediately and mostly transparently.  By 1961 polio cases were down by 97%.  430,000 children in Denmark were vaccinated and none developed polio.  The polio vaccine was ‘new’ but not at all experimental by the time widespread vaccination began.

During the current pandemic, citizens of the world have been asked repeatedly to ‘trust the science.’  Yes.  But trustees of science, including politicians, practicing scientists and physicians, and scientist-administrators at NIH/FDA/CDC and their counterparts in other nations, must at all times be careful, especially when working rapidly and under great pressure, to not oversell what can be done as what must be done.  These mRNA vaccines are commercial products projected to return many billions of dollars to their manufacturers in the very near term.  Eli Lilly received about $320 million, adjusted for inflation, in the first year of the Salk vaccine.

That the COVID-19 mRNA vaccines were oversold from the beginning was most unfortunate.  What could be done rapidly using “cutting edge technology” was considered the only thing that must be done.  The other response was to basically ignore a pandemic, whose underlying disease and sometimes severe sequelae were not yet well understood.  Many scientists in their overweening self-importance did not adhere to the best of their principles, the first of which is that all scientific knowledge is provisional.  Previous scientific research on pathogenic coronaviruses was also largely ignored.  Research on SARS-CoV-2 has lagged.  Non-pharmaceutical interventions such as indoor air filtration were considered only at the margin and then with homemade Corsi-Rosenthal boxes (my two seem to work well).

Public trust is fragile, and once damaged it is difficult to rebuild, in politics and science.  The scientific community did not seem to understand this at critical moments of the pandemic, and this is still true after all these years, based on regular conversation with other scientists.

One Pharma/academic response, in the Bayh-Dole Era they can be one and the same, after ‘The Brand is Damaged’ [2] is found in “Rewriting the Script”:

Aiming to retain global leadership, many researchers in the mRNA sector in the United  States are rethinking how to present their innovations – starting with stepping away from the term ‘vaccine’, particularly when describing mRNA-based cancer treatments.  Although these therapies work like vaccines, delivering genetic instructions to produce proteins that train the immune system, they are designed to treat disease, not prevent it – hence the industry’s pivot towards labels such as ‘immune therapy’.

Companies, including Moderna, are shifting their language.  Last month, Moderna – which not only makes one of the world’s leading COVID-19 vaccines but is also a front runner in personalized cancer therapy – updated the product pipeline on its website, replacing ‘cancer vaccines and therapeutics’ with the more neutral label ‘oncology’.

This should not be necessary, but it is and it is regrettable.  The devil is always in the details, but the potential for mRNA therapeutics is as unlimited as any therapeutic approach can be.  For example, from a post two years ago about An mRNA Vaccine that Works, we discussed a vaccine for pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) that can cure the previously incurable:

Vinod P. Balachandran of Memorial Sloan Kettering Cancer Center (MSKCC) in New York and a large international team took a multidisciplinary approach to identify T-cell antigens in long-term PDAC survivors.  They found that “tumors with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates (indicative of an immune response to the tumor), but neither alone, stratified patients with the longest survival.”  Moreover, neoantigens were found in MUC16, which is also known as CA125.  Cancer Antigen 125 was identified more than 40 years ago as characteristic of ovarian and many other cancers and is used frequently as a clinical marker of cancer.  It is a cell surface glycoprotein (a membrane protein exposed on the outer surface of the cell with sugars attached to it) and therefore readily “visible” to the immune system.

Native immunosurveillance against cancer works, and many tumors are “disappeared” before they cause trouble.  When immunosurveillance can be induced with a vaccine that is specific to a patient’s tumor, the cancer may be cured.  The typically perspicacious NC commenter “The Phoenix” had the following to say during our discussion of the pancreatic cancer vaccine two years ago in May 2023:

Why do we call it “vaccine”?  The treatment looks promising and if it can be done at scale can be part of a multi-modal treatment regimen for cancer. But it’s not a vaccine.

Leave vaccine as it is traditionally understood to prevent disease. Call it something else like “gene induced immune mediated therapy” with a fancy acronym.  Not a vaccine.

Indeed.  But this should not be necessary.  We scientists have retained much respect but have also lost just as much because we have not followed our vocation, which is to examine the natural world with studied disinterest in the search of useful knowledge, while knowing full well that “usefulness” is often recognized long after the research is done. [3]  That political and economic imperatives militate against this is an explanation but not an excuse.  We can do better, all of us – citizens (rather than consumers) by holding scientists to account and scientists by upholding our standards  And both by listening with respect and paying attention to the other.  This is a dream that does not have to be a nightmare.  Otherwise, our future, medical and otherwise, will be much darker than it needs to be.

Notes

[1] That everyone, including those in every scientific sub-discipline, must have a “brand” under the Neoliberal Dispensation has been covered well by Wendy Brown in Undoing the Demos.  Regarding mRNA vaccines, contrary to one self-described inventor in the person of Dr. Robert Malone, these were not invented by an individual.  Malone was first author on the first paper to my knowledge to show that an exogenous mRNA (from a firefly) could direct the synthesis of its cognate protein in cultured mouse cells by making the cell produce the enzyme luciferase that catalyzes the light-producing reaction in the firefly Photinus pyralis.  Why luciferase?  Because light is very easy to measure.  This Nobel Prize in Chemistry recognized the benign chemical modifications of RNA that make mRNA vaccines feasible.  Of course, the disease must be preventable by a vaccine in the first place.  The trials and tribulations of Drew Weissman and Katalin Karikó in procuring institutional and grant support for their seemingly recondite research are also one more object lesson that key discoveries are most often unintentional and that the only way to discover is to support scientists broadly and without the expectation of success in the form of money.

[2] ‘The branding issue for mRNA is not just a problem in the United States…An analysis of social-media data across 44 countries, published last year, found “widespread negative sentiment and a global lack of confidence in the safety, effectiveness and trustworthiness of mRNA vaccines and therapeutics.’

The underlying reference is here: From the Abstract:

The development and rollout of mRNA vaccines during COVID-19 marked a significant advancement in vaccinology, yet public hesitation to vaccination was prevalent, indicating the potential risk that future mRNA-based medical innovations will fail to be adopted…we conducted a social listening analysis to assess attitudes towards mRNA vaccines and therapeutics on Twitter from June 2022 to May 2023, contrasting online perspectives with data from the Vaccine Adverse Event Reporting System.  Our findings reveal widespread negative sentiment and a global lack of confidence in the safety, effectiveness, and trustworthiness of mRNA vaccines and therapeutics, with frequent discussions of severe vaccine side effects, rumors, and misinformation.  This underscores the need for targeted communication strategies to foster acceptance of medical treatments and strengthen public trust in order to enhance societal resilience to future health challenges.

The “global lack of confidence in the safety, effectiveness, and trustworthiness of mRNA vaccines and therapeutics” can be laid squarely at the feet of the scientific community, which in its hubris could not be bothered to remind the people that mRNA vaccines were a necessary experiment under exigent circumstances.  One does wonder if things would have gone differently if this novel approach had been taken with a non-respiratory pandemic likely to yield to a vaccine.  The FDA announced yesterday (20 May 2025) that it “will limit Covid vaccines to people over 65 or at high risk of serious illness.”  Mortality and morbidity associated with long Covid seem to have been flushed down the memory hole, however.  And given that a surge in COVID-19 is currently seen in Southeast Asia, the pandemic is clearly not over.

[3] It is no exaggeration to point out the scientific community skates close to the situation in which the legacy media find themselves – with diminished standing among those who pay attention to what lies beneath.  This explains in part the difficulty of the academic scientific community gaining traction in opposition to the deep cuts in research support of Trump v2.0 that are likely to cause enduring damage to science, scientists, scientific workers, and public health and wellbeing.