Recently, Pfizer and BioNTech released promising
preliminary results of their clinical Phase III trials with 40,000 participants
for their RNA vaccine candidate. This report suggests 90% efficacy for
protection against SARS-CoV-2, the virus which causes the CoVID-19 disease. However,
there is no peer-reviewed publication on this yet.
Since many parameters of this study are unknown, I will focus on the previously published Phase I data1 from the same group and provide some background.
SARS-CoV-2 is an RNA virus. RNA vaccines mimic the viral infection of cells, where the virus uses the cellular machinery to generate viral proteins. In RNA vaccines, the RNA is specifically designed to produce the protein against which immunity is raised. The protein in Pfizer and BioNTech’s CoVID-19 RNA vaccine is the spike protein, which is found on the surface of SARS-CoV-2 and allows it to latch on and enter cells2. RNA-packaged in lipid particles were injected as a vaccine into the deltoid muscle of the participants of the Phase I study. The injected particles are taken up by local cells and eventually RNA is off-loaded into the cellular space outside the nucleus where it is captured by specialized organelles to be translated to protein. The aim of the RNA vaccine was to expose the spike protein to specialized immune cells, which initiate immunity against SARS-CoV-2.
Overall, 195 participants were included in this study and they were separated into two groups, 18-55 and 65-85 years of age, who received either the vaccine (60 and 45 participants, respectively) or a placebo (45 participants in each group)1. Two injections were administered, three weeks apart. Participants were further divided into groups based on the dose received. The optimal dose for each injection was determined based on safety and efficacy. Safety was assessed by local (i.e. pain, swelling) or systemic (i.e.fever, fatigue, GI problems, lymphocyte counts) reactions within 7 days of each inoculation. The efficacy of each dose was determined based on the production of neutralizing antibodies 7 and 14 days after the second dose. These antibodies prevent SARS-CoV-2 to infect host cells. When compared to the levels of neutralizing antibodies found in the blood of patients who recovered from CoVID-19, the vaccine produced 1.7-4.6 times more antibodies in the younger and 1.1-2.2 times in the older group.
Based on these data, the trial moved to phase II/III that will need to be peer-reviewed before being deemed a success. However, the early data communicated in Pfizer and BioNTech’s press release is promising.
Is the speed with which vaccines against Sars-CoV-2 are developing a concern?The advantages of RNA vaccines are the relatively short time for their production and the adaptability of the manufacturing pipeline to other viruses for which genetic information is available.
This ‘vaccine on demand’ approach is attractive for many other potential vaccines which are in the preclinical testing phase for viruses such as influenza, Zika, Ebola3. Therefore, CoVID-19 RNA vaccines are not developed in a rush but are being developed based on the knowledge acquired from other ongoing RNA vaccine studies over several years. This is an important piece of information for those who are suspicious that vaccines will appear on the shelves without a due process for testing. It is also worth noting that in a time of a pandemic, the focus and funding available to develop CoVID-19 vaccines has become the number one priority and this also plays a role in the speed with which vaccines against CoVID-19 are being developed. Another point to consider is that the science behind obtaining and manipulating the genetic code has accelerated tremendously and current methodologies make them more accessible to laboratories around the world. It took four years, in the early 1980s, to identify the HIV-AIDS virus compared to just one month for SARS-CoV-2.
Future of RNA vaccines
The next step in the field of RNA-based vaccines is to utilize RNA that carries information to replicate as well as generate the protein of interest. The advantage of this kind of RNA vaccine is to increase the duration and amount of the protein expressed in the infected cell, so that it will yield a magnified immune response. Such vaccines are in pre-clinical stage for several viruses3. Another customized approach that is of interest for CoVID-19 RNA vaccines is to encode more than one protein of SARS-CoV-2. This is a particularly attractive option given that the immunity generated in CoVID-19 patients not only targets the spike protein but also other proteins of SARS-CoV-24.
Limitation of RNA vaccines
RNA vaccines require very cold temperatures (-80 degrees Celcius) for stability. Although the RNA vaccine manufacturing pipeline seems relatively straight forward, these vaccines (or other RNA-based therapeutics not discussed here) require industrial-scale specialized facilities that are currently located in just a few places, such as Moderna in USA or CureVac in Germany 3. Thus, long distance and requirements for cold temperatures creates challenges for stockpiling and distributing RNA-vaccines globally in the time of a pandemic. New approaches are being reported with lyophilized RNA vaccines so that the stability and bioactivity of the vaccine can be maintained in higher temperatures5
1. Walsh EE, Frenck RW, Jr., Falsey AR, et al. Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. N Engl J Med 2020.
2. Cyranoski D. Profile of a killer: the complex biology powering the coronavirus pandemic. Nature 2020;581:22-6.
3. Maruggi G, Zhang C, Li J, Ulmer JB, Yu D. mRNA as a Transformative Technology for Vaccine Development to Control Infectious Diseases. Mol Ther 2019;27:757-72.
4. Altmann DM, Boyton RJ. SARS-CoV-2 T cell immunity: Specificity, function, durability, and role in protection. Sci Immunol 2020;5.
5. Stitz L, Vogel A, Schnee M, et al. A thermostable messenger RNA based vaccine against rabies. PLoS Negl Trop Dis 2017;11:e0006108.