by Alexis Hubaud
figures by Anna Maurer

Vaccination is key to preventing disease and has been a major advance in public health to eradicate epidemics like smallpox or polio. Vaccines work by mimicking an infectious agent, and by doing so, train our bodies to respond more rapidly and effectively against them. A new class of vaccines, “RNA vaccines”, has recently been developed. RNA vaccines rely on a different way to mimic infection. Compared to previous vaccines, this method is more robust, more versatile, and yet, equally efficient. Therefore, the RNA vaccine technology holds great promise to prevent and treat a wide range of diseases, such as influenza or cancer.

Have you heard about RNA vaccines? This technology recently made the news when the Bill & Melinda Gates Foundation invested $53 million in the German company, CureVac, which specializes in the development of these vaccines [1]. In this article, we will discuss how RNA vaccines work, their main advantages compared to traditional vaccines, and their applications in diseases such as influenza and cancer.

How do RNA-based vaccines work?

Vaccination is the process in which substances called antigens are introduced artificially into the body to stimulate the immune system, the set of cells that protects the body against infections [2,3]. Those antigens are generally infectious agents – pathogens – that have been inactivated by heat or chemical treatment so that they will not cause disease, or they can also be purified proteins from the pathogens. Exposing the body to antigens leads to the production of molecules specifically directed against them, called antibodies. Antibodies create a memory of a specific pathogen (“acquired immunity”) and enable a more rapid and efficient response to a real infection with an active pathogen.

Vaccination has been central in diminishing or eradicating multiple infectious diseases, such as smallpox or polio. However, producing vaccines is a long and complex process, and it has been difficult to implement vaccines against certain pathogens. Thus, designing new vaccines remains a major challenge for public health. To answer this challenge, there have been many improvements to designing vaccines, such as using computational prediction. Development of nucleotide vaccines based on DNA, and the related molecule RNA, is another promising area of progress in the field [4].

In each cell of a living organism, DNA is the molecule that contains the genetic information of the organism [5]. It is composed of a series of four building blocks, whose sequence gives the instructions to fabricate proteins. This process requires a transient intermediary called messenger RNA that carries the genetic information to the cell machinery responsible for protein synthesis. As an analogy, one can see the DNA as a cook book in a library: the recipe is stored here but cannot be used. The commis, or chef’s assistant, first makes a copy (the RNA) of a specific recipe and brings it to the kitchen. The information is now ready-to-use by the chef, who can add the ingredients in the order specified by the recipe and create a cake (the protein).

Figure 1: RNA vaccine technology. An RNA is injected in the body (left). This RNA encodes the information to produce the antigen, which is a protein from a pathogen, that will stimulate the immune system. Inside the cells, the RNA is used to synthesize the antigen, which is exposed to the cell surface (middle). Then, a subset of immune system cells recognizes the antigen and trigger an immune response (direct response and long-term memory) (right).

For a classical vaccine, the antigen is introduced in the body to produce an immune response. However, in the case of DNA- or RNA-based vaccines, no antigen is introduced, only the RNA or DNA containing the genetic information to produce the antigen. That is, for this specific class of vaccines, introduction of DNA and RNA provides the instructions to the body to produce the antigen itself (Figure 1). They can be injected in various ways (under the skin, in the vein or in lymph nodes) and then they can enter our body’s cells. Those cells will use the RNA sequence of the antigen to synthesize the protein [2,6]. After this step, the mechanism is similar to classical vaccines: the antigen is presented at the surface of a subset of cells and triggers the activation of specific cells of the immune system (Figure 2).

The ways in which DNA and RNA vaccines work are similar in many ways, and some of the common steps are described above. However, RNA vaccines have some distinct advantages. One is that RNA-based vaccines appear to perform better than DNA-based vaccines. Another is that they are also safer, as injection of RNA presents no risk of disrupting the cell’s natural DNA sequence. To continue our kitchen analogy, disruption from DNA is like inserting a foreign ingredient in an existing recipe, which can change the resulting dish [2].  Injecting RNA, on the other hand, is like temporarily adding a new recipe in the cook book while keeping old ones untouched, and therefore will not result in surprising changes to existing recipes.

Figure 2: Disease prevention. Vaccination with RNA induces a primary response (top) by instructing the body’s cells to produce an antigen that is presented to the immune system. This activates specific cells, which create a memory for this antigen. Later, when the real pathogen is present (bottom), those cells recognize the same antigen and react rapidly and strongly against the infectious agent (secondary response).

How are they produced?

With the considerable progress in DNA sequencing, it has become relatively easy to determine the genome sequence of pathogens. RNA can thus be produced in vitro, i.e. outside the cells, using a DNA template containing the sequence of a specific antigen. Creating a RNA vaccine also requires some engineering of the RNA to achieve a strong expression of the antigen [4,6].

This is a much simpler process than the culture of virus in eggs. Egg cultures, the more common way of producing vaccines, can provoke allergic reactions; the in vitro production of RNA avoids this possibility. Producing RNA vaccines is also less expensive than producing the full antigen protein [4,6,7].

Another advantage is that the production of RNA-based vaccines is more rapid compared to production of traditional vaccines. This rapid production could be a major advantage in face of sudden pandemics. Moreover, RNA-based vaccines may be effective against pandemics because they also provide more flexibility to prevent or treat pathogens that are rapidly evolving [8,9]. For instance, influenza vaccines have to be tailored each year to specific strains that are most likely to cause disease in the coming season. However, these forecasts have not always been accurate, such as during the winter of 2014-2015, making the influenza vaccine less protective. The World Health Organization estimates it takes approximately five to six months to produce an influenza vaccine, whereas the company CureVac claims that RNA-based vaccines could be manufactured in less than two months at a lower production cost, making it possible to respond to epidemics even as they develop. Therefore, RNA-based vaccines offer a comparatively simple and rapid solution to unpredictable, rapidly evolving pathogens.

While injection of simple RNA can elicit an immune response, RNAs in this form are prone to a rapid degradation. Current vaccines are fragile and can lose their efficiency when exposed at freezing or high temperatures, and must be stored at 35-45°F (2-8°C)[4,6,10]. Thus, preserving the cold chain is a major hurdle for the implementation of vaccine campaign. Fortunately, scientists have found ways to combat this RNA degradation. For instance, they can change the sequence of RNA to make it much easier to store. Furthermore, other molecules can be added to bind the RNA and protect it. Such engineering enables the storage of RNA vaccines at room temperature for at least 18 months. This feature precludes the necessity of maintaining the cold chain, making RNA vaccines particularly practical for developing countries.

What is the current state of the research?

This new exciting technology could be applied to many diseases, and pharmaceutical companies are making major investments in that area. RNA vaccines are still at the pre-clinical or clinical stage, but have yielded promising results. Below, we will explore two examples with the most advanced results: RNA vaccines to treat cancer and RNA vaccines to prevent influenza.

In the field of cancer immunotherapy, “cancer vaccines” take advantage of the expression of specific markers by cancer cells to direct the immune response and attack the tumor. RNA vaccines against prostate cancer, melanoma, and lung cancer (non-small cell lung cancer) are currently in clinical trials. For instance, six different RNAs against proteins produced in excess in tumor cells were used to formulate a vaccine against lung cancer. By taking advantage of the flexibility of RNA vaccine production, scientists can thus produce a vaccine with different antigens which is consequently better at targeting the tumor cells [11].  In the case of the prostate cancer vaccine, a preliminary study showed that injection of those RNAs foster an immune response in most of the patients. Whether this production of antibodies is sufficient to slow down the tumor progression remain to be determined.

Interestingly, because of the versatility of RNA vaccines, they could be tailored to fit the antigen repertoire of each patient tumor. Tumor cells are very different between patients, and this variability is an ongoing an issue for cancer treatment.  An ongoing clinical trial is testing whether RNA vaccines may be effective for addressing variability in melanoma patients: in the trial, each tumor was first sequenced to identify its unique antigen repertoire, and then, a RNA vaccine is tailored to each tumor (Figure 3). This study shows that RNA vaccines could play a major role in this growing field of “personalized medicine” [7]. Moreover, these tailored, on-demand vaccines are practical – the company BioNTech claims that it could be manufactured in 5 months [12]).

Figure 3: Disease treatment (example of personalized cancer immunotherapy). The DNA from the tumor cells is first analyzed (top) to identify antigens specific to the patient’s tumor (Antigens A,B,C). Secondly (middle), a personalized vaccine comprising the specific RNAs for those antigens found in the analysis is injected to direct the attack of the immune system against the tumor (bottom).

RNA vaccines are also being developed to prevent infectious diseases. A vaccine against rabies is currently in clinical trials, while vaccines against influenza, HIV or tuberculosis are still at the research stage. Published results with the influenza vaccine [9] showed promising protection in mice. Indeed, injection of RNA coding for different proteins of the influenza virus induced the production of antibodies, and when the mice were later exposed to the virus, all survived. Similar immune response was observed in ferrets and pigs. All these observations in animals point to a potential use in humans.

The field of RNA vaccines is still nascent. However, their production is flexible and rapid, and recent studies indicate they could be effective against a wide range of infectious diseases and cancers. While their clinical potential in humans remains to be firmly established, RNA vaccines appear to be a promising technology worth watching out for.

Alexis Hubaud is a PhD student in Developmental Biology working at the Brigham and Women’s Hospital / Harvard Medical School


[1] Press statement from the Bill and Melinda Gates Foundation and CureVac
[2] Introductory video about vaccination
[3] Vaccination ingredients from the NHS (UK National Health Service) website
[4] Review about RNA vaccines- Schlake et al. RNA Biology (2012) 9(11):1319-1330
[5] Introductory video about synthesis of proteins from DNA and RNA
[6] Review about the CureVac vaccine – Kallen et al., Human Vaccines and Immunotherapeutics (2013) 9(10):2263-2276
[7] Review about RNA-based therapies – Sahin et al., Nat Rev Drug Disc (2014) 13 :759-780
[8] News article about the use of RNA vaccine against Influenza
Making a Flu Vaccine Without the Virus –
[9] Scientific article on a RNA vaccine against influenza
Petsch et al. Nat Biotech (2012) 30(12):1210-1216
[10] Website from the company CureVac, which specializes in RNA vaccine
[11] Scientific article on a RNA vaccine against non-small cell lung cancer – Sebastian et al., BMC Cancer (2014) 14 :748
[12] Website from the company BioNTech, which specializes in RNA vaccine

126 thoughts on “RNA vaccines: a novel technology to prevent and treat disease

  1. Been reading for hours the SEC filings can you explain why the wordings is the way it is?

    June 30, 2020
    Currently, mRNA is considered a gene therapy product by the FDA. Unlike certain gene therapies that irreversibly alter cell DNA and could act as a source of side effects, mRNA-based medicines are designed to not irreversibly change cell DNA

    Dec. 30, 2021
    Although our mRNA development candidates and investigational medicines are generally designed not to make any permanent changes to cell DNA, regulatory agencies or others could believe that adverse effects of gene therapies caused by introducing new DNA and irreversibly changing the DNA in a cell could also be a risk for our mRNA investigational therapies.

    Seems they are implying that they can introduce new DNA if they want.

    1. mRNA does not change DNA irreversibly or even temporarily. However, you could use RNA to change some gene expressions temporarily, but that is not currently done. Also you could use similar vectors for delivering DNA. That is also not currently done. And even if, the target would be somatic cells. IE the changes would not go to germline and the changes would eventually disappear as the cells die and be replaced. Just like with natural DNA virus infection.

      I hope that clears things up.

  2. None of these ‘mRNA is so great!’ comments aged well. AstraZeneca’s Vaxzervria: thrombosis (with thrombocytopenia!), venous thrombosis in unusual sites such as CVST and splanchnic vein thrombosis. Pfizer Biontec’s BNT162b2 Comirnaty’s myocarditis incidents in young men. JnJ’s Janssen, that caused some issues in young women, enough to get it pulled in some countries, if memory serves, no? Reports left and right about unprecedented and unexplained mortality statistics out of several places, Australia and Japan come to mind… These being official reports, not ‘conspiracy’. The Bradford Hill criteria practically begs to be applied, to ascertain whether there’s causality, as the temporal correlation between mRNA vaccines (be they of the LNP or viral vector persuasion) and death or SAE leaping off the charts appears to suggest. Yet, crickets!
    These hubris filled scientists, who should approach the human immune system with immense respect, got drunk instead on their own (considerable yet insufficient) smarts, and thought they’d test their new toy on humanity… Forget that the IFR of this virus was barely high enough to constitute a pandemic: an mRNA vaccine in every arm! Forget that the young immune system made child’s play of CV19 infection: vaccinate at birth! Forget that we’re counting the guy hit by the bus, or the 95 year old dying of dementia as CV19 deaths. And now, it’s- forget the Pfizer trial documentation, can we please have 75 years to work on releasing it?
    Look, kudos for working on mRNA technology, it’ll be undoubtedly welcome by patients who unfortunately have terminal cancers… But to MANDATE it on humanity for a virus whose effect is barely worse than that of influenza… I hope to see folks answering for this in the near future.

    PS: One of the official Moderna SEC filing documents does state “Currently, mRNA is considered a gene therapy product by the FDA.”

  3. Hi everyone.

    I’m not a doctor nor scientist, but a molecular biologist just showed this litterature in a scientific congress in my country. I’d love to know your professional thoughts on these topics. Thanks

    First, she says that in Comirnaty there are parts derived by humans and that conventional protocols in RNA interference recommend not to use sequences in common with the host genome.

    Then, she shows few studies:

    Fire et al. (1998) – revealed sequence-specific gene silencing induced by synthetic, short, double-stranded RNAs of ~21 nucleotides in lenght (in C. elegans)

    Elbashir et al. (2001) – proved the same mechanisms in mammalian cells

    Jackson et al. (2003) – revealed OFF-TARGET GENE REGULATION by RNAi, with interference even with very limited identity (11-15 contiguous nucleotides)

    Zhang et al PNAS Vol. 118 No. 21 (April 2021) – Demonstrated that Reverse-transcribed SARS-CoV-2 RNA can integrate into the genome of cultured human cells and can be expressed in patient-derived tissues

    She ends saying that “exogenous RNA can also modify DNA organization affecting its functioning.”

    All this is in contrast with the article, can anyone explain or debunk, this studies or theory?

    Thanks in advance,


  4. I’d be interested in knowing if there is any legitimacy to spike protein shedding from covid 19 vaccinated individuals to unvaccinated individuals? Or just the spike protein shedding.

  5. I’ve shown you your writing skills and your blog looks great. Is this a paid theme or did you edit it yourself? Ayyyy keep going with good quality. Reading a good book.

  6. I have been looking into mrna products and came across a website that outlined the agreement between Moderna and SEC to fund their research and “fast track” the development of the mrna vaccine. While reading through it, I found a very concerning sentence under the “Risk Factors” portion of the document within paragraph 52(or you can put the following quote into the find on page function): “….mRNA is highly unlikely to localize to the nucleus, integrate into the DNA, or otherwise make any permanent changes to cell DNA.”. Infact, much of what I read in that agreement was concerning. However, my question is, why is the phrasing relating to whether or not mrna can cause irreversible changes in your DNA “highly unlikely” and not a definite “can’t”? Is it because of the lack of research?

Leave a Reply

Your email address will not be published. Required fields are marked *