Scientific-based answers for the popular questions around Pfizer-BioNTech and Moderna mRNA vaccines
By: Avil Deved
Tags: Vaccines, Coronavirus, Trump, Covid 19, News

1.- How is it that these vaccines were approved faster than others?

Throughout the history of humanity, many types of vaccines have been created. The main types of vaccines include live attenuated, inactivated, recombinant subunit vaccines, and nucleic acid vaccines (Figure 2). Currently, it isn’t possible to prepare and test a vaccine before a new viral threat spreads throughout the World; thus, there are no universal vaccines for any virus. The various types of vaccines have different production pipelines. Manufacturing time is relevant to mitigate an emerging pandemic because all the vaccines, regardless of how long they take to be manufactured, must pass for the following stages before approval for human application: academic research, pre-clinical studies, testing in Phase I trials (dozens of people), Phase 2 (hundreds of people), and Phase 3 (thousands of people). Once the vaccine has been approved, it is necessary to scale up production by building factories in various locations to increase the efficiency of rolling out the newly approved vaccines. From the time of the initial outbreak, in this case, Wuhan (December 2019), until the vaccine production, testing, approval and wide distribution is a critical factor to control any outbreak, prevent future pandemics and global economic crises, and ultimately and most importantly save as many lives as possible.

Figure 2.- Main types of vaccines. a) live attenuated, b) inactivated, c) recombinant subunits and d) nucleic acids. The virus, SARS-CoV-2 is composed of various proteins such as the Spike protein and others that enclosed the viral genetic information necessary for the virus to replicate inside human cells. Nucleic acid-based vaccines utilize the DNA or mRNA sequences of specific set of viral proteins. The various types of vaccines make use of these viral elements (whole weakened or inactivated virus, viral proteins or viral genetic information) to train our immune system before it gets infected with the virus. A challenge with the virus after immunization will result in a protective response orchestrated by the trained immune system.

Vaccines based on mRNA are the most advanced generation of vaccines and take the shortest time to be produced. For example, according to the CDC, the live attenuated vaccine production for measles took over ten years (2). Aside from its efficacy promoting an effective immune response in the host, we cannot afford ten years to produce a candidate vaccine for every new disease. These ten years do not consider pre-clinical studies or clinical trials. Speed for vaccine manufacture saves millions of lives.

Luckily, Biotechnology has allowed the production of subunit and nucleic acid vaccines in a shorter time. For nucleic acid vaccines, such as the Pfizer-BioNTech and Moderna mRNA vaccines, the only required element to manufacture the candidate vaccine and start the entire rigorous procedure of testing is the target’s nucleic acid sequence, in this case of the spike protein from the SARS-CoV-2 virus.

Currently, Whole Genome Sequencing technology allows to sequence entire genomes of practically any biological entity within hours. On March 10th, the RNA genome sequence of SARS-CoV-2 (called 2019-nCoV at that time) was reported by the World Health Organization (WHO). It was determined that this sequence differed in 380 amino acids relative to the previously known SARS virus (3). The next day that the genome sequence of SARS-CoV-2 became available, the German BioNTech company started collaborations with the American Pfizer pharmaceutical. The rapid multi-national partnership was a critical move in launching a vaccine candidate as soon as possible. On the same day, March 11th, it was clear that the novel coronavirus (SARS-CoV-2) was a global threat, and the WHO declared COVID-19 a pandemic (Figure 3).

Figure 3.- Timeline of significant moments of the COVID-19 pandemic in the year 2020. Specific moments in favor of vaccine development (green) and the pandemic (red) are shown. The bottom section shows four stages of the pandemic during 2020. Speed was essential to mitigate the pandemic, and mRNA vaccines have this essential quality against any pandemic. Notice that the three required phases of clinical trials were performed throughout the year, leading to FDA approval for the Pfizer-BioNTech and Moderna vaccines.

A robust platform that identifies a new threat’s genetic information and rapidly manufactures a vaccine will be essential to prevent future pandemics. To this end, the rapid development and large-scale deployment of mRNA vaccines are very appealing (4). It also becomes important to mention that massive testing (alternatives described here back in March) at an early phase of the outbreak would have been pivotal to mitigate domestic spread within countries. A combination of massive testing, early isolation, and free treatment of positive cases was essential for the few successful countries in mitigating the pandemic, such as South Korea, without lockdowns (5).

In summary, a fast response is an essential factor to mitigate the pandemic. The development of vaccines also should have this property. Fortunately, biotechnological tools enable the manufacture of vaccines in a shorter time (~1–1.5 years of mRNA vaccines against ten years of more traditional vaccine approaches). The FDA approval of mRNA vaccines in this fateful 2020 is the glimpse of hope for 2021. For the near future, speed will be again the key for saving lives; this time, the rate for global vaccine distribution. We cannot make the same mistakes from early 2020, such as the disinformation about masks, lack of strategies for massive testing, and the slow public response to control spread. Countries must fight disinformation and facilitate vaccination pathways for their population. The sooner they do this, the more lives they will save, and the sooner their economies will be recovered.

2.- How do these mRNA-based vaccines work?

Each type of vaccine (Figure 1) has the main principle to present an antigen to our immune system cells (Antigen Presenting Cells or APC). This presentation will awake the desired memory in our immune system (T cells activation) to produce a robust response against the real virus in case of infection (plasma or activated B cells). The antigen could be the whole virus (live attenuated, inactivated) or a fraction of the virus (subunit vaccines).

The beauty of nucleic acid-based vaccines, such as mRNA vaccines, is that our own body is in charge of looking at these genetic instructions and translating them into specific antigens that will train our immune system against SARS-CoV-2. The mRNA molecules are much simpler to make than proteins in the laboratory. Thus, the manufacture of mRNA vaccines requires less time with the same protective response. Figure 4 shows the components of the mRNA vaccines from Moderna and Pfizer-BioNTech. The only required element is the mRNA encoding for the prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein (shown in green in Figure 4).

Figure 4.- mRNA Pfizer- BioNTech and Moderna vaccines activates the innate and adaptive immunity required to protect us from the SARS-CoV-2 virus. Both vaccines are based on the same principle. The mRNA will be translated within the APC cells (such as dendritic cells, shown in purple), which will present the fragments of the viral protein that will be recognized by naïve CD4+ T cells (shown in blue), activating them into helper T cells (effector). The same will occur with cytotoxic T cells (shown in green). B cells (shown in orange) can also serve as APC. T helper (CD4+) cells will activate B cells to convert them into plasma cells. Plasma cells can produce specific antibodies that correspond to the antigen presented by T cells. Effector T cells (CD4+ and CD8+) have additional functionalities to activate further the innate immunity (not fully shown in the picture for illustrating purposes, a meaningful type of innate immune cells against viruses are the NK cells). The specific antibodies will bind very specifically to different sites of the spike protein. A potential infection of the SARS-CoV-2 to a vaccinated organism will result in the virus’s neutralization by these produced antibodies.

3.- Fact-check of claims around these mRNA vaccines

a) The mRNA vaccine modifies your DNA

False. Our genome (DNA) is compacted inside the nucleus. mRNA is transcribed from DNA and not the other way around. Besides, mature mRNA is translated into functional proteins in the endoplasmic reticulum ribosomes (ER). The fact that the DNA is transcribed into mRNA, and this into proteins, is known as the central dogma of Molecular Biology. In Eukaryotes, such as humans, the transcription (DNA to mRNA) involves an “mRNA processing” step. This step is required to form mature mRNA. Mature mRNA contains elements shown already in the mRNA used for the vaccines that stabilize the molecule, such as 5’-cap, poly-A, and removal of introns. The mRNA of the vaccine is a molecule ready to be translated into proteins and cannot be integrated into our genome.

b) The mRNA vaccines cause infertility

No scientific basis for this claim, and the comparative technical analysis shown below indicates that this claim is False. This claim says that syncytin-1, a placental protein, is very similar to the Spike protein of SARS-CoV-2; therefore, the antibodies that would neutralize the virus will damage the organs with this protein, causing infertility. Synctin-1 is encoded by the ERVW-1 gene, which belongs to the family of HERV genes (HERV = Human Endogenous Retroviruses) already present in the human genome. This family of genes is ~5% of the human genome and contributed to human evolution (6, 7).

Comparative technical analysis between Synctin-1 and Spike proteins.

Here, we aligned the two proteins to show potential similarities. As shown in Figure 5, the area with the highest score in the alignment contains only three shared amino acids between the two proteins. However, the most frequent size of an epitope (specific site within the antigen binds to an antibody) considering the minimum contiguous amino acid sequence containing all antibody-contact residues is 50–79 amino acids (8). This is enough evidence to discard undesired antibody binding to the synctin-1 protein.

Figure 5.- Alignments of Synctin-1 and Spike proteins. The first alignment shows the area of the two proteins with the highest score. This score is a parameter to identify similar proteins based on the % identity, gap frequency, and length of the aligned area. Considering all these similarity parameters, the alignment with the highest score (56.0) had a 30.2% identity relative to the Spike protein with only three shared contiguous amino acids. In contrast, the most frequent number of contact residues for an antibody-antigen binding event is at least fifty.

The antibodies made by the plasma cells after immunization (vaccination) will bind with very high specificity to various sites within the spike protein to neutralize a potential viral infection. This alone also suggests that it is improbable to observe undesired antibody binding to synctin-1 or any other protein within our body. Even in a hypothetical case of an equimolar ratio of these proteins and antibodies, the total protein size of 1273 amino acids (spike) and 538 amino acids (synctin-1), and the total available residues of each protein that can be targeted by our own produced antibodies after immunization (1273 amino acids for spike protein and 3 amino acids for synctin-1) decrease, even more, the chances of any unspecific antibody binding event.

Overall, we can conclude that this placental protein does not have enough similarity to the Spike protein of SARS-CoV-2 to cause antibody cross-reactivity nor infertility.

c) The mRNA vaccines were made with fetal cells

False. One of the main advantages of mRNA vaccines is their rapid manufacture because they do not require cell lines for their production.

d) The vaccines side effects are of greater risk than having COVID-19

False. While all vaccines cause some side effects on occasions, none of them will represent a higher risk than catching the virus. Mild side effects (e.g., headaches and fatigue) are often observed after applying any vaccine. This won’t be worse than having the symptoms of the damage caused by the uncontrolled replication of SARS-CoV-2 inside your body.

Moderna and Pfizer-BioNTech phase 3 clinical trials collected data from 30 350 and 38 000 participants, respectively. Both vaccines utilize two doses. The study evaluated all types of side effects in all participants after each dose. It determined that after the first dose, only 0.2% of the Moderna trial participants and 0.0% from the Pfizer-BioNTech trial developed severe adverse reactions. Both studies highlighted that these data of adverse reactions were insufficient to determine a causal relationship with the vaccine (9, 10). People with some history in terms of allergic reactions should consult their physician, and the CDC also recommends that people that might develop some allergic reaction in the first shot should not get the second dose (11).

4.- What should we be doing before getting vaccinated?

Keep reading information based only on scientific facts. The sources must provide the respective references, and these references must be from a trustworthy source such as scientific articles, WHO, or CDC websites.

Spread the word, share this article, discuss every time you hear some potential misinformation or false claim. The vaccine will save millions of people’s lives, and you can contribute to genuinely saving lives by merely checking trustworthy sources and communicating scientific-based facts.

It is uncertain when you will have access to the vaccine and when most of the population will be immune to SARS-CoV-2. Thus, mask, social distancing, not traveling, and not participating in large gatherings are still the only way to mitigate the pandemic.

There is light at the end of the tunnel, but we don’t know how long this tunnel will be.

Stay focused!

References

1. J. Cohen, As COVID-19 vaccines emerge, a global waiting game begins. Science (80-. ). (2020), doi:10.1126/science.abg1793.

2. CDC, Ncird, “Immunology and Vaccine-Preventable Diseases — Pink Book — Principles of Vaccination,” (available at https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/prinvac.pdf).

3. A. Wu, Y. Peng, B. Huang, X. Ding, X. Wang, P. Niu, J. Meng, Z. Zhu, Z. Zhang, J. Wang, J. Sheng, L. Quan, Z. Xia, W. Tan, G. Cheng, T. Jiang, Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China. Cell Host Microbe (2020), doi:10.1016/j.chom.2020.02.001.

4. N. Pardi, M. J. Hogan, F. W. Porter, D. Weissman, mRNA vaccines-a new era in vaccinology. Nat. Rev. Drug Discov. (2018), , doi:10.1038/nrd.2017.243.

5. D. Lee, K. Heo, Y. Seo, COVID-19 in South Korea: Lessons for developing countries. World Dev. (2020), , doi:10.1016/j.worlddev.2020.105057.

6. M. Cáceres, J. W. Thomas, The gene of retroviral origin syncytin I is specific to hominoids and is inactive in old world monkeys. J. Hered. (2006), doi:10.1093/jhered/esj011.

7. K. Khodosevich, Y. Lebedev, E. Sverdlov, Endogenous retroviruses and human evolution. Comp. Funct. Genomics (2002), , doi:10.1002/cfg.216.

8. J. W. Stave, K. Lindpaintner, Antibody and Antigen Contact Residues Define Epitope and Paratope Size and Structure. J. Immunol. 191, 1428–1435 (2013).