A nurse draws from a vial of Johnson & Johnson’s COVID-19 vaccine in Los Angeles, March 25, 2021. Photo: Reuters/Lucy Nicholson/File Photo

Two COVID-19 vaccines, Covaxin and Covishield, are currently at the forefront of India’s fight against COVID-19. Earlier this week the Drug Controller General approved another viral vector vaccine, Sputnik V, developed by the Gamaleya Institute in Russia, for restricted use. The health ministry is also expected to approve yet another viral vector vaccine, AdV26 by Johnson & Johnson, in time. So India will soon be employing three viral vector vaccines in its large-scale COVID-19 vaccination drive, in which hundreds of million doses will be administered.

Recently, many reports of rare blood-clotting disorders associated with the administration of the AstraZeneca vaccine have emerged from many European countries and Australia. As a result, the regulators in more than 20 European countries suspended the vaccine’s distribution. Six cases (out of 6.8 million doses administered) of clot-related disorders were also reported from the US, associated with the Johnson & Johnson vaccine, leading the government to call for a temporary pause of the rollout. Sputnik V is being used in around 60 countries but there have been no similar reports in the public domain thus far.

A team of doctors in Kerala conducted a survey among more than 5,000 healthcare workers in India over a week and found that 65.9% had at least one post-vaccination symptom. This reflects the high reactogenicity of the vaccines. In most cases, the symptom was related to the Covishield vaccine. India’s National AEFI Committee1 had also recorded 180 post-vaccination deaths until March 31, 2021, and that three-fourths of the deaths had happened within three days of vaccination – most of them, again, after taking Covishield.

However, causality assessments are available only for 10 deaths in the public domain. Many of the AEFIs and deaths reported in India bear striking similarities to those recorded in the EU.

The viral vector vaccine

These reports have brought the spotlight on the safety of viral vector vaccines. Specifically, are these vaccines safe, and if so, are they being unduly targeted? It’s worth answering this question because the AstraZeneca shot in particular, called Covishield in India, has been at the centre of the WHO’s plan to roll out around two billion doses to 92 nations by the end of 2021.

During the phase 3 trials of both the AstraZeneca and Johnson & Johnson vaccines, there were reports of serious AEFIs – multiple sclerosis and transverse myelitis – after their respective administrators temporarily paused these trials. There was also a case of transverse myelitis in India during Covishield’s bridging trial. These were early warning signals. However, the researchers who analysed these events ultimately deemed them to be unrelated to the vaccine.

The reports of sudden deaths in many vaccinees in India and blood-clotting disorders associated with the administration of AstraZeneca shot in many countries suggested the probable role of a vaccine-induced immune mechanism.

The administration of mRNA vaccines’ doses have also been associated with serious AEFIs, including deaths in a few European countries like Norway and Germany, and the US. And once again, there is little data about Sputnik V in the public domain that could aid an independent analysis.

Limitations of viral vector vaccines

All three viral vector vaccines employ an adenovirus vector. The vector is a virus that carries a piece of the novel coronavirus to human cells. There, the piece sets off a chain of reactions that ultimately produces an antigen specific to SARS-CoV-2 and which invites the attention of the immune system. The AstraZeneca vaccine uses a chimpanzee adenovirus; the Johnson & Johnson vaccine uses human adenovirus 26; Sputnik V uses two different human adenoviruses: 26 for the priming dose and 5 for the booster dose.

Adenoviruses are one of the most genetically diverse DNA viruses and cause non-life-threatening infections in a diverse range of hosts. They can also reach the central nervous system and cause neurological ailments. The meninges – tissues that cover the brain and spine – are rich in dendritic cells, which capture the antigen and initiate an immune response; the brain tissue itself is devoid of dendritic cells, however.

Adenoviruses are excellent vectors for delivering large genes or vaccine antigens to target host tissues. In gene therapy, researchers find them particularly useful for testing experimental therapies for certain otherwise untreatable neurological diseases. The few cases of neurological illnesses during the AstraZeneca and Johnson & Johnson trials also demonstrate the higher affinity of the corresponding adenovirus to the central nervous system.

Viral infections that damage the central nervous system may also cause the immune system to attack both viral and human proteins in the body due to similarities between them, an event called autoimmunity (‘auto’ stands for ‘self’). Indeed, homology2 between human and viral proteins is an established factor in viral or vaccine-induced autoimmunity.

So can the presence of adenoviruses as a vector increase the risk of autoimmunity? We need to study this association in detail, since the human experience with these vectors, including the chimpanzee adenovirus, is paltry.

There are also some other major drawbacks of employing adenoviruses as vaccine vectors.

High dose of viral vector – Adenoviruses are known to induce robust innate immune responses in their hosts. But a major drawback of the use of adenoviruses is the induction of an undesirable innate immune response. The dose of vectors used in these vaccines is also very high, around 1010 viral particles. These two factors together explain the high reactogenicity that these vaccines can evoke.

Preexisting immunity in humans – Adenovirus infections are common among humans, and nearly each one involves some level of adenovirus-specific antibodies. The resulting high seroprevalence of these antibodies is a major roadblock in adenovirus vector vaccine development. That is, the presence of these antibodies limits the number of doses of such vaccines that can be administered, and reduces the efficiency with which genes delivered by the vaccine can be expressed in the body.

This is the reason why the development of most adenovirus vector vaccines started with a single dose. The Johnson & Johnson shot and China’s CanSino adenovirus 5 vector shot are both single-dose. In addition, though researchers have modified these vectors to not be able to replicate within the human body, they may trigger the generation of some immune response after the first dose. This again limits the efficacy of further booster doses. This is why it’s not advisable to get more than one booster dose of these vaccines.

(Researchers observed the interference of vector-induced immunity in the AstraZeneca vaccine trial. Vector-associated antibodies take some time to wane, so this is one reason why a second dose administered after a longer interval induces a higher immune response.)

To sidestep preexisting immunity against human adenovirus vectors, the developers of the AstraZeneca vaccine used a non-human chimpanzee adenovirus. Since these viruses don’t infect humans, neutralising antibodies against them are less common.

However, despite this low seroprevalence, preexisting cross-reactive T cells against many antigens are still a major concern. According to the American Academy of Allergy, Asthma & Immunology, “Cross-reactivity … occurs when the proteins in one substance (typically pollen) are similar to the proteins found in another substance (typically a food). For example, if you are allergic to birch tree pollen, you may also find that eating apples causes a reaction for you.” The negative effects of cross-reactive T cells on the AstraZeneca shot may have impacted its immune response and overall efficacy.

The Sputnik V vaccine, in its phase 3 trial, reported a higher efficacy than the AstraZeneca, Johnson & Johnson and CanSino vaccines. (In its defence, the Johnson & Johnson vaccine was tested in the latter half of last year’s pandemic in the countries where SARS-CoV-2 variants were surging.) The Russians’ technique of using different adenovirus vectors for the priming and boosting doses was clever. This strategy seems to be effective in circumventing preexisting immunity against adenovirus vectors.

The AstraZeneca vaccine and blood clots

In Europe, at least 222 suspected cases have been reported among 34 million people who received their first dose of the AstraZeneca vaccine. More than 30 have died. Similar cases have since been reported from the US with the use of the Johnson & Johnson vaccine, but with extreme rarity: one case out of one million doses administered. Are these effects really the cause of the vaccines?

The answer could be ‘yes’, but with a catch. Many researchers now believe that these people had unusual antibodies that triggered clotting reactions, which then used up the body’s platelets and blocked blood vessels, leading to potentially deadly strokes or embolisms. This condition has been called vaccine-induced immune thrombotic thrombocytopenia (VITT) – and is another manifestation of autoimmunity induced by vaccines.

Scientists have advanced many hypotheses to explain this phenomenon.

Extracellular DNA triggers thromboses – Among the 50 billion or so viral particles in each dose, some may break apart and release their DNA. DNA is negatively charged, and could bind it to platelet-factor-4 (PF4), which has a positive charge, in the blood. The resulting complex could then trigger the production of antibodies, especially when the immune system is already on high alert because of the vaccine. Free DNA itself can signal the body to increase blood coagulation. This is how our body deals with injured cells.

Preexisting antibodies – Alternatively, the anti-PF4 antibodies may already be present in the body and the vaccine may just boost them. Many healthy people harbour such antibodies, but they are kept in check by an immune mechanism called peripheral tolerance. We know the AstraZeneca vaccine produces a lot of inflammation. This strong inflammatory response could break down peripheral tolerance in some people with PF4 antibodies, leading to VITT.

Cross-reaction between anti-spike antibodies and PF4 – Some experts have suggested that antibodies against the novel coronavirus’s spike protein, which many vaccines seek to elicit, somehow cross-react with PF4. This could spell trouble for nearly all COVID-19 vaccines. However, most experts don’t support this hypothesis.

Risks of other vaccines

Thus far, there haven’t been many reports discussing any similar vis-à-vis the two mRNA vaccines, made by Pfizer and Moderna. However, there is a potential risk with nucleic-acid-based vaccines – including mRNA, DNA and viral vector vaccines – to induce autoimmunity thanks to the development of autoreactive antibodies. Recently, in Israel, one news report claimed a sudden increase in the number of cardiac ailments, described as a “murky wave of heart attacks”, following mass administration of the Pfizer mRNA vaccine.

One possible explanation is autoimmune myocarditis, a condition that is also often underdiagnosed. Healthcare workers have been attributing the ‘sudden death’ reports to adverse effects that may not be directly related to mRNA vaccines even as they may be the result of vaccine-related myocarditis leading to fatal arrhythmias, acute-onset heart failure with cardiogenic shock and pericardial effusion with cardiac tamponade.

In sum, adenovirus vector and mRNA vaccines may have common autoimmune risks. The supra-physiological expression levels of spike proteins in some individuals who receive nucleic acid-based vaccination might share in the development of these autoimmune reactions.

Many sudden deaths and deaths occurring in the first three to seven days of taking the Covishield vaccine in India could also be explained by this autoimmune mechanism. But we will need more studies and surveillance to be sure.

Does this mean we should abandon the use of all viral vector vaccines? The answer is a resounding ‘no’. The serious adverse events that have been reported are extremely rare. And these vaccines, particularly AstraZeneca’s Covishield, is one of the world’s most important defences against the pandemic. In the vast majority of cases, its benefits outweigh its risks.

This said, it would be better if we can attach a label to these vaccines saying there is a minuscule risk of autoimmune reactions that may prove fatal. After all, we already know that not all vaccines are 100% safe. We know about the rare side-effects of vaccine-associated paralytic polio with the oral polio vaccine and intussusception with rotavirus vaccines – but they are still life-saving and have proved their worth to the country many times over.

Next, we need to identify risk factors for thrombosis in COVID-19 disease and after vaccination. Individuals who may be at higher risk of developing these rare immune reactions should be forewarned.

Third, the techniques used to develop different COVID-19 vaccines, especially those based on nucleic acids, should focus on innovative methods to decrease their potential autoimmunity.

Experts have suggested that cutting the vaccine dose in half – a simple strategy – could reduce the risk while also stretching vaccine supplies. In the AstraZeneca vaccine’s phase 3 trials, a small number of people accidentally received a lower dose and had fewer side effects in general. Perhaps the lower dose is less likely to trigger the sort of strong inflammation that boosts PF4 antibodies as well.

Finally, but importantly, we must institute a strict post-vaccination surveillance system to report any serious adverse effects, especially among those who have contracted COVID-19 after vaccination. We know that another rare condition called antibody-dependent enhancement, in which vaccinated people run a risk of more severe disease than those who are not vaccinated, exists.

Researchers discovered acute intussusception3 after receiving the rotavirus vaccine a year after the vaccine’s rollout. It took almost 40 years for us to detect vaccine-derived poliovirus, a rare adverse event of the oral polio vaccine. These are still early days for the COVID-19 vaccine rollout. We need to be extremely vigilant to detect and investigate any safety signals. At stake is not just this or that vaccine but the people’s faith in the entire vaccination process.

Dr Vipin Vashishtha, MD, FIAP, is a consultant paediatrician at the Mangla Hospital and Research Centre, Bijnor.



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