[version 1; peer review: 1 approved with reservations]
No competing interests were disclosed.
Vaccines have played a central role in dealing with COVID-19 pandemic. Now regulatory agencies in USA and around the world have begun approving vaccination for kids. Long term safety profile of live attenuated viral vaccines, inactivated viral vaccines and peptide-based vaccines are well studied in children, are safe and can play a central role in controlling the spread of COVID19 in children. But the long-term safety profile of viral vector-based vaccines is not studied. In the present correspondence we highlight the possibility of random insertional mutagenesis and potential side effects, which might be evident after long-term. Regulators must take into consideration the possibility of insertional mutagenesis and conduct long term studies before approving the viral vector vaccines in children, so that the public have trust in the regulatory agencies and are compliant towards vaccinating their children with safe and effective vaccines.
COVID-19 infection which is caused by (SARS)-related coronavirus species 2 or SARS-CoV-2 has caused more than 545,226,550 confirmed cases and 6,334,728 deaths as of 30 June 2022.
There are four main types of COVID-19 vaccines which are either approved or are in clinical trial. They are broadly classified into: 1) Nucleic acid vaccines (DNA & RNA vaccines), 2) Viral vector vaccines, 3) Protein subunit vaccines and 4) Whole virus vaccines.
On 5
th May 2022 FDA restricted the use of the J&J shot because of the threat of rare but serious blood clots, to individuals eighteen years and older who cannot access other vaccines.
The viral vector vaccines uses a viral vector to deliver viral spike protein DNA into the cell like modified chimpanzee DNA adenovirus which is an icosahedral viruses with double-stranded DNA (dsDNA) genome in the case of Astrazeneca COVISHIELD,
Studies have shown that plasmid DNA or linear dsDNA as in the case of a (linearized) plasmid or PCR products undergo homologous recombination or may integrate randomly at any nicked sites in the genome.
There are reports of Human adenovirus type 12 (Ad12) inducing primitive neuroectodermal neoplasia’s in virus-inoculated newborn Syrian hamsters T637 cell lines, secondary to the random integration of Ad12 DNA into T637 genome.
When lentiviral vector was used to shuttle the IL2 gene into Severe combined immunodeficiency (SCID) infants, four of the nine infants developed leukemia between three and six years after the treatment, with the first case being clinically evident after 3.5 years of therapy. In these infants the leukemic process was attributed to LMO-2 proto-oncogene up-regulation secondary to integration of the wild type IL2RG gene along with the vector into the genome.
On the other hand Stephen
While the jury is still out regarding the occurrence of the viral vector vaccine associated random insertional mutagenesis, extreme care should be exercised while recommending viral vector vaccine in children and infants, especially when alternative safer vaccines like mRNA vaccines and inactivated viral vaccines are available. Given the first case of leukemia was evident after three and half years of gene therapy (from three and half years to six years post gene therapy four out of nine infants developed leukemia), it’s important to conduct long term safety studies for viral vector vaccines before recommending these viral vector vaccines in children.
No data.
We agree with the authors that the recommendation of vaccinating children below 5 years of age against Covid-19 is debatable. There is no unanimity as far as mandatory vaccination of healthy young children against Covid-19 is concerned. We know that the incidence of severe disease in young infants is extremely low. Most infants have asymptomatic disease. With the emergence of novel variants and improved testing, there has been a higher incidence of COVID-19 disease reported among children and neonates. Despite this, the proportion of young children with severe disease has not increased. Even the incidence of MIS-C has decreased considerably since the advent of the Omicron variant.
We also agree with the authors’ suggestion that there is a need to assess the long-term and short-term safety profile of viral vector vaccines in the population, especially the young pediatric population. Many national vaccine-recommending authorities have mentioned the risks of administering these viral vector Covid-19 vaccines in this age group. Similarly, the CDC though has recommended vaccination of young kids aged 6 months onwards, has not recommended viral vector vaccines for this category of children.
Thrombosis with thrombocytopenia syndrome (TTS) has been reported in young adults following adenoviral-vector vaccines; however, there are no such reports in children.
Rare cases of myocarditis and pericarditis have been reported after vaccination in older children and adolescents who received the mRNA vaccine. In these reports of myocarditis, the incidence was found to be higher after the second dose of the mRNA vaccine
The main concern raised by the authors is related to the theoretical long-term risk of inadvertent insertion of viral vector DNA into the human DNA following vaccination. Earlier, at the time of the introduction of these viral vector vaccines, in some societies, people have become sensitized against the potential short- or long-term side effects of foreign DNA being injected into humans.
Before debating the issue of SARS-CoV-2 vector vaccine-induced integration of viral DNA, let us first discuss the issue of whether the SARS-CoV-2 virus gets its DNA integrated into human host DNA during acute infection.
We know some viruses insert their genetic material into the cells they infect, but it generally remains separate from the cell’s DNA. During a viral infection, genetic material (DNA or RNA) from the virus is there inside our cells, but most viral infections don't then leave DNA that becomes part of the genome
However, in certain cases, it happens. HIV, for instance, has a reverse transcriptase, which copies the viral genetic material back into the genome. But viruses like the coronavirus or influenza don't have that enzyme.
However, one study indicated that SARS-CoV-2 RNAs can be reverse transcribed in human cells by reverse transcriptase (RT) & that these DNA sequences can be integrated into the cell genome & subsequently be transcribed.
The authors emphasize that their results don’t imply that SARS-CoV-2 establishes permanent genetic residence in human cells to keep pumping out new copies, as HIV does.
A study published in 2021 showed that SARS-CoV-2 RNA can be reverse-transcribed and integrated into the genome of the infected cell and be expressed as chimeric transcripts fusing viral with cellular sequences (Zhang L ,et.al., 2021 [Ref: 1]). Other experts disbelieved this finding. They find that a very low frequency of identified chimeric events suggests that SARS-CoV-2 integration into the host genome is unlikely. (Parry R,et.al.,2021 [Ref: 2])
However, some experts show that fragments of SARS-CoV-2’s genome integrate. They observed that since it is all pieces of the coronaviral genome, it cannot lead to infectious RNA or DNA and therefore it is probably biologically a dead end. So, they conclude that this kind of integration would be extremely rare if it does indeed happen.
So, there is still no unrefutable evidence of SARS-CoV-2 virus genome integration into human DNA following natural infection. The actual integration of viral DNA molecules and adenovirus vector DNA will likely be chance events whose frequency and epigenetic consequences cannot with certainty be assessed. The extent to which adenoviral gene products might become co-expressed with the SARS-CoV-2 spike glycoprotein upon vector-vaccine injection into human deltoid muscles remains un-investigated.
Eventually, it will come down to weighing the possible risks of genomic insertions of vaccine-associated foreign DNA and unknown levels of vector-carried adenoviral gene expression versus protection against the dangers of Covid-19.
The extent to which adenoviral gene products might become co-expressed with the SARS-CoV-2 spike glycoprotein upon vector-vaccine injection into human deltoid muscles remains un-investigated. At present, we cannot gauge their possible effects on the human organism, if expressed.
However, as stated above, the above apprehensions are only of theoretic considerations since viral vector vaccines are no longer promoted in the pediatric population owing to their association with some other serious risks like VITT and autoimmunity. However, the discussion is not completely superfluous since this risk may be associated with adults and elderly vaccinated people also.
-Dr Puneet Kumar, MBBS
-Dr Vipin M. Vashishtha, MBBS, MD
Are arguments sufficiently supported by evidence from the published literature or by new data and results?
Partly
Is the conclusion balanced and justified on the basis of the presented arguments?
Partly
Is the rationale for commenting on the previous publication clearly described?
Yes
Are any opinions stated well-argued, clear and cogent?
Yes
Reviewer Expertise:
Pediatrics, vaccines, immunology
We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above.