Vaccines: Busting the myths and laying out the science

Close to a year into the pandemic, vaccines seem to be on everyone’s mind. It is nothing short of a tremendous feat that we now have not just one but three approved vaccine candidates either already deployed or preparing to be deployed around the world. Considering the standard vaccine (or drug) development timeline of ca. 5–10 years, it speaks to scientists’ brilliant abilities when able to work singularly towards one goal, have the funding available, and the political will in place for science to succeed.

However, this dichotomy of the “usual” vaccine timeframe and the 10-month COVID19 vaccine development timeframe has resulted in some murmurs of mistrust in certain sections of society across the world. Furthermore, the advent of the mRNA vaccines and the novel technology associated with it compared to previous vaccine platforms have also contributed to the same. Vaccines are the predominant method by which we can tackle this pandemic which is now stepping into its 2nd year. If we are to have any hope of getting back to a “normalcy” and saving millions of lives, widespread immunity through vaccine immunization is essential. As such, we at oDoc have prepared a short primer to address your most pressing questions about the COVID19 vaccines currently available.

Let’s address the elephant in the room, part 1: were the vaccines rushed?

Short answer: no safety steps were cut.

Long answer: A drug development pipeline consists of several steps: 1) a preclinical trial and 2) a clinical trial. Clinical trials are broken into a) Phase I b) Phase II and c) Phase III. As depicted in the diagram below, these phases take differing amounts of time, involve differing subjects, and focus on differing objectives.

The preclinical stage involves accurately modelling the drug’s desired effect and getting initial information on its efficacy and safety. The vaccine candidate is tested in vitro (inside test tubes) and in vivo (animal) to get the necessary information. If successful, the drug candidate moves to the clinical phase. Success rates are around 32% during this stage, aka of 100 drugs, only 32 will move to the next stage. Given this high level of risk, it’s often hard to find funding for this phase of drug discovery and development.

The three phases of the Clinical trial have different objectives. Phase 1 is designed to assess the drug’s safety and tolerability in a small group of healthy human subjects with a 75.1% success rate. Phase 2 is designed to test drug efficacy and continue safety testing in a larger group of human subjects with a 50% success rate.

Finally, Phase III which follows the gold standard format of trials, the randomised control trial with a large group of volunteers (usually a few hundred but in the 40–50,000 range for the COVID19 vaccines) split into a placebo control group and the vaccine candidate group. These trials are expensive, time-consuming and challenging to run and aim to evaluate the drug’s risk-benefit across a cross-section of the target population.

None of these steps was cut for the Pfizer, Moderna or AstraZeneca vaccine development processes. Due to the wide prevalence of the disease and the political & economic focus on developing a vaccine, ample subjects were ready to be enrolled in trials and ample funds ready to be invested in the process. Both culminated in the rapid development process and enabled the deployment of the vaccines for emergency use as early as January 2021. If anything, we may be encouraged that if the money & interest were there, science could move much faster than it’s currently able to.

Part 2, are the vaccines safe?

Short answer: The detailed studies which took place over ca. 9–10 months have shown them to be safe. Phase 3 studies for all the major vaccine candidates are still on-going. Furthermore, side effects from vaccines occur very soon after vaccinations, and as trials have been tracked since April 2020, these reactions would have already been reported had they happened. They didn’t.

Long answer: BioNtech and Moderna have been working on their proprietary mRNA technology long before COVID19 came into the arena. Scientists and researchers view this technology as a game-changer for drug development — cutting down development time and making mRNA candidates cheaper and more customisable than the traditional drug candidates.

Pfizer/BioNTech

Due to this customisable nature, BioNtech were able to develop ca. Twenty candidates for early-stage research as soon as Chinese laboratories released the genetic sequences of Sars-Cov-2 in Jan 2020.

As shown in the timeline below, they then teamed up with Pfizer and began Phase I and II trials simultaneously with four vaccine candidates in the race. This stage consisted of a small number of subjects. Once the FDA reviewed the data, it moved to concurrent Phase II and III trials with the lead vaccine candidate, BNT162b2 and 44,000 subjects across the US, Germany, Turkey, South Africa and Brazil.

Pfizer/BioNTech have done full safety assessments for over 38,000 study participants and saw side effects that were common transient reactions to any vaccinations (e.g. injection site pain). 2% of subjects had headches and a further 3.8% fatigue with all complaints resolving within a few days after vaccination.

Moderna

The Moderna vaccine candidate, mRNA-1273, is also based on mRNA technology. The shortlist of vaccine candidate was ready to enter into the research process by January 16th, an amazing two days after the Chinese laboratory released the genetic sequence but long before the first cases were detected in the US. Phase I trials began in mid-March with Phase II & III running concurrently from end July with 30,000 participants in the US.

Full safety assessments have been conducted with the most common adverse events being injection site pain after 1st dose and fatigue, body pain, headache and redness at the injection site after the 2nd dose.

AstraZeneca

The Oxford vaccine (as it’s commonly referred to) is adenovirus-based however the vaccine candidate wasn’t developed initially for Sars-Cov-2. The vaccine candidate, ChAdOx1 was developed and tested for various diseases, including on Ebola during the 2014 outbreak and Zika in 2016. These extensive trials may not have resulted in a successful candidate against these specific diseases but have helped researchers ascertain the vaccine platform’s safety.

After adapting ChAdOx1 to COVID19, early clinical trials did not report adverse events. The candidate moved to Phase I trials in early April (with staggered starts across the globes), and ultimately successful results were published in July. Phase II/III trials began in August in four cohorts: UK, Brazil and South Africa and final results were published in November. In total, ca. 23,000 participants were enrolled in the study. Safety assessments showed similar reactions to the Pfizer vaccine above, but no severe reactions were observed.

Next question: Do mRNA vaccines alter my DNA?

Short answer: mRNA (or messenger RNA) doesn’t alter DNA. mRNA doesn’t hang around in your body for long and disintegrates after a short period and is safer than traditional vaccines. Live vaccines inject small amounts of the live virus, and attenuated vaccines inject the inactivated virus into your body. With mRNA, we are only injecting a blueprint of a specific recognisable part of the virus.

Long answer: A vaccine aims to teach the body how to recognise the virus. When a virus infects a host cell, the virus releases its RNA, which enters the host cell nucleus and replicates itself using host cell machinery. Viral mRNA then transcribes viral RNA into proteins which then reassemble as more viruses. These newly synthesised viruses enter into the host blood stream and chaos ensues.

1. mRNA vaccines do not constitute the entire viral structure. Much like our blueprint is our DNA, the virus blueprint is its DNA or RNA. We use this blueprint to recreate the virus’ outer shell (or the spike proteins). The human equivalent would be to use your DNA to recreate your skin.
2. mRNA creates proteins, not DNA. Once the candidate enters the host cell, the mRNA is released. The mRNA does not enter into the nucleus where the DNA is hosted. Helpers like ribosomes come alongside the mRNA strands within the cell cytoplasm. Like construction workers laying brick after brick following an architect’s blueprint, they start to assemble amino acids in the mRNA chain’s order. These assembled amino acids form proteins — spike proteins to be precise.
3. The spike proteins do not cause any harm on their own because they cannot replicate. That ability lies within the virus’ RNA or DNA, and we didn’t recreate that. The spike proteins are then sent to the cell surface and held out (like waving a flag from a window) or released into the bloodstream.
4. Vaccines help our immune system arm up against a potential intruder. Our immune system recognises Sars-Cov-2 via the spike protein and by sending some “placebo” spike proteins into the system gives them an early start in being prepared for potential infection. Members of our immune system are usually wandering around the bloodstream looking for potential intruders. When these sentries come across the spike proteins, they launch an immune response.
5. All three vaccines activate both arms of our immune system: the innate and acquired arm. Once the immune system recognises the intruder, it will start to create antibodies to fight against it and more importantly, activate memory cells that will remember this knowledge for a time.

mRNA technology isn’t brand new — it has been in formulation for many years with human trials for mRNA based cancer vaccines running in 2011. The scientific community is excited about the Pfizer/BioNtech & Moderna mRNA vaccines’ success for several reasons. Its rapidly deployable (researchers created Moderna candidates within two days of the COVID19 genetic sequencing), cheap (as it doesn’t require massive investment in the candidate development phases) and specific (we can hone in one area with great precision).

Stay tuned for our next post where we look at the efficacy data of each of the major vaccines currently available for EUA.

Article first appeared at https://www.odoc.life/2021/01/26/vaccines-busting-the-myths-and-laying-out-the-science/