Anti-vaxxers need tutorials in Biology101

Letter from Dr Musa Mohd Nordin (paediatrician), Dr Zulkifli Ismail (paediatrician) and assistant professor Dr Mohammad Farhan Rusli (Public Health physician),Kuala Lumpur

Content keywords: Covid-19 vaccines; anti-vaxxers

THE results of the Health Ministry's survey in December 2020 showed that 16% of Malaysian adults refused the Covid-19 vaccines while 7% were hesitant. Up until two days ago (March 23), 97.5% of our adult population above 18 years old have had two doses and 66% have been boosted. And 91.5% of our adolescents have been inoculated with two mRNA vaccine doses.

We have undoubtedly reassured and convinced many of the vaccine sceptics. More critically, this transformation of the Malaysian vaccine psyche has conferred the country a very powerful immunity wall to face the threat of the super transmissible Omicron BA.2 sub-variant, which now makes up 27% (and climbing) of the emerging variants.

The Omicron BA.2 variant has rapidly become the dominant strain in Denmark, the United Kingdom and India, and is continuing to spread in the United States, Europe, China and Asia. It has overwhelmed the healthcare services in Hong Kong.

Malaysia’s immunity wall, induced by both vaccine and natural immunity, has led to the lifting of many of the previously imposed restrictions and opening of the borders, which would undoubtedly boost the national economy.

India is forecasting a potential fourth wave in June 2022. As the Delta wave has shown before, we need to pay close attention to countries like India to enhance our preparedness strategies. Rather than wait and see, we must think and plan ahead of the virus by upping our weapons in this battle, i.e. vaccination, apart from other mitigation efforts and a measured and proportionate transition to the endemic phase.

It is disheartening to note that there still exists a minute fraction of our citizens who are resentful of these vaccine successes in preventing Covid-19 associated hospitalisations, ICU admissions, deaths and long Covid. These recalcitrant, teeny-weeny but noisy persons and a sprinkling of NGOs remain sceptical of the pivotal role of vaccines in protecting our healthcare capacity and making the nation safe and secure enough to allow it to transition towards endemicity.

They continue to spread misinformation about the vaccines, especially the mRNA types. Their fear mongering polemics was given a kiss of life with the results of a Swedish study, which allegedly suggested that the vaccines entered the human DNA.

The mantra that vaccines "alter your DNA" has resonated since the first smallpox vaccine was introduced in 1796. Satirical paintings showed cows growing out of the human body, depicting that the human anatomy had been changed by the smallpox vaccine. This was the historical forefathers of the anti-vaccine movement.

Contrary to popular belief, mRNA vaccine technology, which came to the attention of the lay public only in the past two pandemic years, is not brand new. It was discovered in 1960 and the safe delivery of the mRNA to humans was facilitated by the successful development of the mRNA nanoparticle envelope in the 1990s.

There are at least nine mRNA vaccines in phase one to three trials, including influenza, rabies, cytomegalovirus, varicella, respiratory syncytial virus, human metapneumovirus, zika and nipah viruses. The mRNA-HIV vaccine in phase 1 trials is the most recent addition.

There are also mRNA therapeutics against auto-immune disorders, cancers and inborn errors of metabolism (e.g. phenylketonuria and glycogen storage diseases).

Quite obviously, the anti-vaxxers are either ill informed of these advances and developments in mRNA technology over the past 30 years or have chosen to hide it from the public domain and fool the public into believing that it is a two-year-old technology.

Voluminous research and scientific knowledge, global scientific collaboration and massive financial investments have powered the development of two of the world’s most effective vaccines against SARS-CoV-2, the mRNA Pfizer and Moderna vaccines. This was achieved in March 2020, within two months of the Chinese authorities making public the genomic sequence of the SARS-CoV-2 virus.

Initially granted emergency use authorisation (EUA) by the United States Food and Drug Administration, both the Pfizer and Moderna mRNA vaccines have now acquired full approval, which means they are both safe and effective like the conventional vaccines. This should inspire confidence and help ease vaccine hesitancy. It will also debunk the notion that they are still "experimental vaccines".

To date, 10.8 billion doses of mRNA vaccines and other Covid-19 vaccines have been administered, making it one of greatest historical milestones in science, medical research and clinical applications.

Can the anti-vaxxers name any other scientific landmark or public health intervention that surpasses this stellar mRNA vaccine achievement towards saving human lives, mitigating morbidity and eventually getting us out of this pandemic (apart from clean and safe drinking water)?

To clear the science and sanitize the twisted anti-vaxxers’ biology, it needs to be reiterated that the final common pathway of the mRNA vaccines is not novel. They are presenting a (dead) sub-unit protein called the Spike Protein to the human body to elicit an immune response, which is the production of protective neutralising antibodies and long-term memory B and T cells.

This is not much different from the use of (dead) sub-unit proteins in the Hepatitis B, Human Papilloma Virus and Influenza vaccines. Sinovac and Sinopharm vaccines instead present (dead) inactivated lots of the entire coronavirus to the human body.

What is novel is the cutting edge strategy to use mRNA to enter the cytoplasm and NOT the nucleus, as the anti-vaxxers allege, where the DNA is housed. The mRNA then sits on the ribosomes (outside the nucleus) and makes the (dead) sub-unit Spike Protein.

The mRNA is a very fragile molecule, and that is why it needs to be stored in arctic temperatures. It does not linger in our cells for very long. Enzymes called ribonucleases (RNases) rapidly degrade the mRNA. It is also not possible for the mRNA to move into the nucleus of a cell as it lacks the signals that would allow it to do so.

The (dead) sub-unit Spike Proteins also do not last long in the body. Like other proteins in the human body, they may last up to a few weeks. The immune system quickly identifies, attacks, and destroys them because it recognises them as not being part of you. They are mainly in the lymph nodes and are cleared from the body.

The recent laboratory study from Sweden that has generated excitement among anti-vaxxers concluded that the BNT162b2 (mRNA Moderna vaccine) can be reverse transcribed to DNA in liver cell lines known as Huh7, which gave rise to the concern that BNT162b2-derived DNA may be integrated into the host genome and could affect the integrity of the human DNA.

A careful scientific examination of this artificial, in-vitro study will show that it is flawed on multiple fronts. We shall try to unpack this Swedish

experiment for our simple understanding.

Firstly, the virus SARS-COV-2 is an RNA virus. It does not have the capability nor the intelligence to produce a DNA transcript, or in layman’s terms, it cannot make a DNA copy of itself. Without this potential (unlike the HIV retrovirus), it cannot incorporate itself into the host’s genome.

Similarly, the mRNA of the Moderna and Pfizer vaccines cannot be reversed transcribed, i.e. make a DNA copy of itself, to allow its insertion into the human DNA.

Students of “O” Level Biology will tell you that the vaccine mRNA and the human DNA reside in two different parts of the cell. Our DNA, the

genome, stays in the nucleus while the vaccine mRNA is only delivered by the nanoparticle envelope into the cytoplasm (the space outside the nucleus). It never enters the nucleus. This is because there are no transporter molecules that we are aware of that can direct the mRNA into the nucleus.

We think the anti-vaxxers badly need tutorials in Biology101!

Thirdly, the Swedish petri dish experiment used cancer cell lines. The Huh7 cell line was derived from a liver cancer organ. These cancer cell lines surely must behave very differently from normal cell lines. The Swedish researchers themselves admitted: "The cell model that we used in this study is a carcinoma (cancer) cell line, with active DNA replication which differs from non-dividing somatic cells. It has also been shown that Huh7 cells display significantly different gene and protein expression including upregulated proteins involved in RNA metabolism.”

They should have utilised a more genetically normal cell line. Cancer cell lines, which can propagate indefinitely, are surely not representative of a normal genome. They should have considered, for example, a number of cell lines from the respiratory tract, lining of the blood vessels or even from the umbilical veins. This is obviously a basic failure in investigational science studies.

Fourthly, the Swedish investigators used abnormally high amounts of vaccine in their studies, which is non-physiological (not within the normal range required for the metabolic equilibrium in the human body). They injected two micrograms for 200,000 cells, which is very excessive, when the physiological dose in the mRNA vaccine is 30mcg for the entire human body, which consists of 30 trillion cells).

Finally, a close analysis of the study shows that the investigators did not provide any clinical evidence of integration of the vaccine mRNA into the cell DNA. They did not undertake any test to confirm the insertion of the mRNA into the cell DNA. Even if it was shown to be integrated into the DNA, we cannot be sure of its significance because cancer cells are well known to overexpress LINE1 (long interspersed nuclear elements), a naturally occurring reverse transcriptase. And the excessive amounts of vaccine doses used would surely cause anomalous results.

In fact, there was an earlier experiment that also claimed to show SARS-CoV-2 could undergo reverse transcription and integrate into the genome of the infected cells. However, the results were never reproduced. This almost certainly points towards artifacts in the experimental conditions that are neither naturally relevant nor sustainable.

This excitement over flawed experiments highlights a scientifically problematic idiosyncrasy of the anti-vaxxers. Their grasp of basic biology is very suspect, let alone their understanding of double blind randomised controlled vaccine efficacy and safety trials, vaccine efficacy in clinical trial versus vaccine effectiveness in real world experience, pharmacovigilance and post-licensure marketing surveillance for safety, the concept of risk benefit analysis and much more.

They have, however, perfected the art of cherry-picking bits and pieces of research to sensationalise their pseudoscience and medical quackery. They are overnight Google expert doctors and scientists who spend all their time on cyberspace unlike the real experts who labour in the research laboratories, conduct vaccine safety and efficacy clinical trials, publish their outcomes in peer-reviewed journals, present them to global and national regulatory agencies, and undertake post-licensure pharmacovigilance studies.

Until and unless the authorities take stern and uncompromising action against these few noisy persons and NGOs, our naïve lay public will continue to be bombarded with fear mongering, fake news and misinformation.

The progress that the nation has thus far achieved to prevent Covid-19 morbidities and mortalities, transition to endemicity and achieve some semblance of national safety, security and near-normalcy will be thwarted by these recalcitrant and irresponsible persons and NGOs.

DR MUSA MOHD NORDIN

DR ZULKIFLI ISMAIL

and ASSISTANT PROFESSOR DR MOHAMMAD FARHAN RUSLI

Kuala Lumpur