Over the last year, news of COVID-19 has dominated the headlines. Caused by SARS-CoV-2, a coronavirus, the global pandemic is now associated with 116 million diagnoses worldwide and 2.57 million deaths. While many were unsure, initially, how to deal with the introduction of this novel virus, some are hopeful that we are now heading towards more protective options: the advent and authorization of vaccines.

In the United States, there are currently three authorized vaccines: from Pfizer and BioNTech, Moderna, and Johnson & Johnson. Outside of the United States, vaccines are being created by AstraZeneca PLC and the University of Oxford, among others. As the vaccines roll out, with a goal of having most individuals vaccinated by the end of summer, a common refrain is that the vaccine you should get is whichever one is available to you.

But in actuality, for members of the rare disease community, the conversation may not be so simple. This comes down to how the vaccines were developed: messenger RNA (mRNA) vaccines or those, as the Wall Street Journal describes it, “developed with gene-based technologies.”

While there is no conclusive evidence to determine whether or not one option is better than the others, some prior studies suggest that patients with rare diseases are better suited for mRNA vaccines, like those developed by Moderna or Pfizer & BioNTech, over those developed using viral-vector technology, which is often used in gene therapy and could potentially cause issues at a later date.

The Three Vaccines

Although the AstraZeneca vaccine also uses viral-vector technology, this article will focus more on unpacking the three vaccines authorized for emergency use within the United States. As described by StatNews, there are a number of differences between the Moderna, Pfizer & BioNTech, and Johnson & Johnson vaccines. To begin:

• The Pfizer vaccine is indicated for use in people ages 16+. Currently, the Johnson & Johnson vaccine, as well as the Moderna vaccine, are only indicated for use in those ages 18+. While Johnson & Johnson does not appear to be doing additional testing, Moderna is currently testing its vaccine for those ages 12-17.
• The Pfizer vaccine was 95% effective in preventing symptomatic cases of COVID-19 after 2 shots. After two doses, the Moderna vaccine was 94.1% effective in preventing symptomatic COVID-19.
  • Alternately, the Johnson & Johnson vaccine chose not to focus on symptomatic COVID-19, but on how well the vaccine conferred protection against moderate-to-severe COVID-19. Ultimately, it was 66% effective against moderate-to-severe infection, and 85% effective against severe infections, following a single dose.
• None of the vaccines have been tested in those that are pregnant or lactating, although the companies hope to perform additional testing soon.
• Side effects include injection site reactions, fatigue, muscle and joint pain, and headache. Severe cases of anaphylaxis have been linked to the mRNA vaccines, although one case of anaphylaxis has also been linked to the Johnson & Johnson vaccine.

But perhaps the most important consideration, and the one most often left out of the conversation, is whether the mRNA vaccine or viral-vector vaccines are better suited for those receiving them.

mRNA vs. Viral Vectors

The National Human Genome Research Institute describes messenger RNA (mRNA) as:

a single-stranded RNA molecule that is complementary to one of the DNA strands of a gene [and acts as] an RNA version of the gene that leaves the cell nucleus and moves to the cytoplasm where proteins are made. During protein synthesis…a ribosome moves along the mRNA, reads its base sequence, and uses the genetic code to translate each…codon into its corresponding amino acid.

In short, the mRNA vaccine is able to deliver some genetic code to cells. In this case, the mRNA vaccines attempt to teach the immune system that the spike proteins which sit on the surface of the SARS-CoV-2 virus and help it infect cells are foreign invaders. If the immune system recognizes this, it can then create antibodies to the spike proteins and also prevent infection or severe disease. Interested in learning more about how mRNA vaccines work? The CDC explains here.

As the Wall Street Journal explains, viral-vector technology works in a different way. Researchers use an adenovirus or adeno-associated virus to deliver genetic material straight to cells:

Covid-19 viral-vector vaccines are made by engineering a harmless type of virus, such as an adenovirus that can cause the common cold, to carry a gene from the coronavirus into the cell. The vaccine’s DNA payload instructs the body’s cells to begin making a protein from the coronavirus, [provoking] an immune response to protect a vaccinated person if they are later exposed.

Prior to developing the COVID-19 vaccine, Johnson & Johnson used this same technique to create an EMA-approved Ebola vaccine.

A Brief History of Viral-Vector Technology

There are a number of promising advantages conferred by viral-vector technology, such as being able to develop and quickly manufacture vaccines. For example, while prior vaccines required the use of inactivated viruses and took years to develop, the three vaccines were all developed in a matter of months. Additionally, viral-vector technologies are able to create and activate antibodies. So there’s no wonder scientists have been exploring viral-vectors for medical use since the 1970s.

However, viral-vector vaccines have not always been successful, explains the Wall Street Journal. In 2007, pharmaceutical company Merck & Co. developed an experimental viral-vector vaccine to protect against HIV. Unfortunately, the vaccine failed, as “those in the study with pre-existing immunity to the vaccine’s adenovirus strain seemed to have a higher susceptibility to HIV infection.” In later vaccine attempts for other conditions, such as Ebola, Merck & Co. focused on using viral-vectors like vesicular stomatitis not commonly found in humans.

Vaccines and the Rare Disease Community

Because of the prior failures in viral-vector technology, a concern arises regarding the COVID-19 vaccines and those with rare diseases. In a webinar spearheaded by the National Organization of Rare Diseases (NORD), FDA commissioner Stephen Hahn stated:

It is really hard to study vaccine efficacy and safety in one rare disease, because we just don’t have enough people with those diseases to come to significant conclusions.

Although the FDA, CDC, and a number of rare disease advocacy organizations state that they believe viral-vector vaccines would be safe for those with rare diseases, it brings up an interesting question, particularly for those with genetic conditions: would exposure to a viral-vector potentially limit one’s ability to pursue gene therapy in the future, or make gene therapy less effective?

Gene Therapy

The Mayo Clinic describes gene therapy as:

altering the genes inside your body’s cells in an effort to treat or stop disease.

For example, scientists can replace defective genes with a functional copy; activate or inactivate a gene; or use genes to improve immune function. The gene therapy is delivered using (you guessed it!) viral vectors.

Currently, there are a number of conditions which can be treated with gene therapy, or for which gene therapy is being explored.

For example, some hemophilia treatments depend on the therapy being delivered via wild-type adeno-associated viral (AAV) vectors, such as parvovirus.

Spark Therapeutics also created a hemophilia treatment, SPK-8011, using a specially engineered AAV vector.

LUXTURNA, for patients with biallelic RPE65 mutation-associated retinal dystrophy, uses AAV2.

Gene therapy is also being looked into for severe combined immune deficiency (SCID), certain types of cancer, sickle cell anemia, Gaucher disease, and even Alzheimer’s disease!

Altogether, gene therapy offers an opportunity for patients with rare diseases to find hope for future cures or more targeted treatment options. Thus, it can be concerning to wonder whether or not the COVID-19 vaccine could cause an issue.

Alternately, those who have previously received gene therapy may not achieve the vaccine’s intended effect. The Wall Street Journal also noted that:

a viral-vector COVID-19 vaccine developed in China didn’t perform as well in some people during testing because subjects had pre-existing immunity to the underlying virus that was used.

Overcoming Obstacles

Theoretically, there is a way to create effective vaccines using viral vectors that would not cause issues for those who have received, or may receive, gene therapy. This is by using a virus from another species, such as a chimpanzee adenovirus, which would greatly cut down on the chance that anyone had previous exposure.

In the development of past Ebola vaccines, Johnson & Johnson created effective vaccines using Ad26, another adenovirus not common in humans. They used the same development process to create their COVID-19 vaccine. The company’s idea was:

to employ Ad26 to carry DNA into human cells to instruct them to make their own spike protein. That would trigger production of immune-system antibodies to fight off the actual virus in a vaccinated person, by binding to the spike protein and preventing it from entering cells.

Admittedly, Ad26 has not been used in gene therapies before and is novel in vaccine use. But despite that the NORD webinar explained that “The likelihood of something happening here, where one of those vaccines would preclude you from getting a gene therapy, is pretty much non-existent,” the question still remains whether receiving a viral vector vaccine, like that of Johnson & Johnson or AstraZeneca, could present an issue in the future.

Safety & Vaccines

Another burgeoning issue is whether or not viral vector vaccines are as safe as their mRNA counterparts. While there has yet to be a problem with the Pfizer, Moderna, or Johnson & Johnson shots, recent reports are spreading worries over the AstraZeneca shot. After at least one woman was hospitalized for a pulmonary embolism and another died, some are concerned that the AstraZeneca shot could increase the risk of dangerous blood clots. Because of this, many countries are already suspending the AstraZeneca shot from use. This comes amidst assurances from both the European Medicines Agency (EMA) and World Health Organization (WHO) that the shot is safe, and that no evidence from clinical trials suggests that it would cause an issue.

However, because AstraZeneca does use a viral vector, it is a potential cause for concern. Additional insight is needed.

Sarepta Therapeutics also notes that there are limits on how patients within gene therapy clinic trials may receive their vaccines. Ultimately, the company does not believe that the viral vector vaccines will interfere with future inclusion into gene therapy trials. However, CDC guidelines do state that treatments given in gene therapy clinical trials may reduce vaccine efficacy.

Advocating for your Needs

If you are a part of the rare disease community, you are probably no stranger to advocating for your own needs. Ultimately, there is no way to determine whether receiving one vaccine over the other will present more of a risk. However, if you are concerned about receiving a viral vector vaccine, remember to advocate for yourself within the healthcare setting. This means:

• Speaking to your healthcare provider or medical team about your condition, including risks associated with COVID-19 infection.
• If you have a genetic disorder, asking what types of gene therapy are currently used (or may be used in the future).
• Asking any questions or raising any concerns about the use of viral vectors.
• Asserting your limits and your comfort zone in which vaccine(s) you are willing to receive.