Vaccines Still Offer Protection from Mutated Virus

National Immunization Awareness Month falls in August and is now perhaps more poignant than ever. In the past year, millions of people the world have become intensely aware of the power and benefits that vaccination can have as they receive their doses of the COVID-19 vaccines, helping get the world back to “normal.”

Simulate to stimulate: how do vaccines work?

Vaccination is the process of training your immune system to fight off disease that it hasn’t previously come into contact with. To fully appreciate how vaccines work, it is important to understand the underlaying cellular biology. A vaccine typically delivers an antigen (derived from the disease we want to vaccinate against) into the body to simulate infection and stimulate an immune response. When an antigen is detected, dendritic cells have the job of processing and transporting the antigens to the lymph nodes. At the lymph nodes the antigens are presented to specialized T cells, activating them. These activated T cells can then go on to stimulate B cells, which in turn produce antibody secreting plasma cells and memory B cells. Thus, your body is now equipped with the tools to fight that specific disease if you were to come up against it in the future. However, many diseases such as SARS-CoV-2 or influenza for example are constantly mutating.

Why do viruses mutate and what does this mean for SARS-CoV-2 vaccinations?

Viruses’ aim in life is to infect hosts and replicate, and it is this continuous replication that makes them prone to mutation, a result of copying errors. With time, or indeed good/bad luck, these errors can lead to alterations to viral antigens making them stronger, resistant, or obsolete. In the case of influenza for example, copy errors in this virus lead to new strains that overcome the projection provided by vaccination, which is why annual immunization is offered. With regards to SARS-CoV-2, from what we have observed thus far it is a virus that is relatively slow to mutate compared with other RNA viruses, mutating at a speed approximately four times slower than influenza. This should be good news with regards to the longevity of current vaccinations, but should not encourage complacency; after all SARS-CoV-2 is still relatively new and has many unknowns. One variant of SARS-CoV-2 that is currently the most predominant strain in the U.S. has been named the delta variant. The delta variant emerged due to mutations on the N-terminal domain and the receptor-binding domain of the SARS-CoV-2 spike protein. The delta variant has been found to be more contagious and may cause more severe disease. The science shows that after two doses of current available vaccines there is still protection against the delta variant, and so vaccines are still the most effective way to minimize spread and severity of disease. These results were published in the NEJM here.

I had the pleasure of chatting with Professor Larry Corey, MD, from the Fred Hutchinson Cancer Research Center. Dr. Corey is a world-renowned expert in vaccine development, and he had the following to impart on SARS-CoV-2, the delta variant, and future perspectives:

Dr. Mulholland: Current vaccination regimes seem to be effective toward the delta variant after two doses. Given your experience, do you believe further and immanent vaccination will be required for emerging variants, and will this be sustainable?

Dr. Corey: The data for six month or later booster immunizations are just beginning to emerge. For the mRNA vaccines the data look quite encouraging; boosting doses are well tolerated and appear to enhance pre-boost neutralizing antibodies almost 50-fold; levels being higher after the boost than after primary two-dose immunization. This appears the case with ancestral or other strains and there is uncertainty whether variant boost is advantageous. Whether this approach will actually improve efficacy and how much durability we get from this boost is as yet unknown. I think it’s critical for us to evaluate efficacy of booster doses and evaluate what types of B cell memory as well as T cell responses one elicits from such an approach. Such studies will help us determine if B cell repertoire analyses say homologous boosting varies / narrows over time or whether memory responses are enhanced if we also include variant priming or boosting.

Dr. Mulholland: In your opinion, will the clinical success of the mRNA COVID-19 vaccines pave the way for the vaccination of other deadly diseases?

Dr. Corey: In general success begets success. Most of us including me would not have predicted the mRNA technology to be the leader over other approaches. I think we are starting to see a movement of mRNA vaccines in other hard-to-develop vaccine-like diseases. So, I think the answer is a clear yes!

Gene therapy beyond COVID-19 vaccines

Beyond vaccines, the world of gene therapy is exploring many other exciting avenues for the treatment of SARS-CoV-2. One such project is being undertaken by Northern Irish company pHion Therapeutics. pHion Therapeutics was founded in 2017 by Professor Helen McCarthy, who is based in the school of pharmacy at Queen’s University Belfast (UK). pHion Therapeutics makes use of a unique cell penetrating peptide called RALA which can quickly condense all nucleic acids (DNA, mRNA, siRNA etc.) and other anionic small molecules (such as chemotherapies) to form extremely stable nanoparticles possessing the ideal biophysical characteristics to cross cell membranes, deliver cargo with high efficiency, and have low related toxicity.

pHion Therapeutics is currently working on the development of an exciting RNAi therapy option for COVID-19 that makes use of the RALA peptide. The system is being optimized for the transient knockdown of the ACE2 receptor with the nanoparticles preferentially being delivered to lung tissue. Thus, this technology has fantastic potential in the treatment of acute COVID-19.

This is just one of several exciting projects pHion Therapeutics is currently working on, with the technology also being utilized for oncological, regenerative, and vaccination applications, so watch this space!

Take home messages

As more and more variants of SARS-CoV-2 emerge, adapted vaccination interventions will be required. Presently, current vaccinations are showing efficacy towards the delta variant, but this is not guaranteed for future strains, but with the current vaccine technology now widely used for the repression of COVID-19 (as well as other diseases) coupled with the exciting alternative gene therapy options being developed by companies such as pHion Therapeutics, the future is hopeful for the control of this disease. Finally, for those interested in learning more about how mRNA vaccines work, please watch this video from ASGCT’s Patient Education Program.

Dr. Mulholland is a postdoctoral research scientist in cancer genetics and junior research fellow (Somerville College) at the University of Oxford. He is a member of the ASGCT Communications Committee.