“This is an unprecedented pandemic, and extraordinary times call for extraordinary measures;” these are the words of Kiran Mazumdar-Shaw, chief executive of Biocon — India’s top biotherapeutics firm, on concerns about the safety of the COVID-19 vaccines being used widely to inoculate people around the world. In case anyone had
doubts on her sincerity, she also promised to be one of the first to take the shot when these vaccines eventually find their way into India.
The successful commercialisation of COVID-19 vaccines “at lightning speeds” is, undoubtedly, a most extraordinary achievement. Developing a vaccine within a timeline of 8-9 months has hitherto been absolutely unthinkable. Never before has anybody even imagined being able to launch a vaccine in less than a year from the time the pathogen was first identified. Conventionally, vaccine development is one of the most time-consuming activities for drugmakers. It usually takes several years for a company to come out with an effective vaccine.
What has helped scientists buck this trend this time is a hitherto untested vaccine platform technology. The two vaccines currently approved for emergency use, from Pfizer/BioNTech and Moderna, rely on messenger RNA or mRNA technology to simulate a SAR-CoV-2 attack on the body.
mRNA vaccines can be developed and deployed comparatively quickly and easily, as can be seen in this case.
No time was lost between the publishing of the genetic sequence of SARS-CoV-2 in January 2020 by Chinese researchers and the mRNA vaccine makers kick starting their epoch-making efforts.
BioNTech did not miss even a day, recounted CEO Ugur Sahin, while sharing the origin story of the company’s COVID-19 vaccine at a UN COVID-19 Summit in early December. The German firm, he said, commenced the development of the vaccine on the very first working day after the weekend of January 24 when he came to know about the virus in detail.
Likewise, scientists at Moderna and the National Institutes of Health too were able to finalise the design for a vaccine in just two days.
These researchers were more than sure the mRNA approach can hasten the otherwise years-long process of developing a successful vaccine to counter the pandemic virus.
But, at the same time, the scientists were not totally oblivious of the fact that they were experimenting with a novel concept with no model or precedents to guide them or emulate. No commercially available vaccine used mRNA technology or provided clinical data for the researchers to leverage. Nor were there any reports on the safety of mRNA candidates in large scale clinical studies.
Nevertheless, the first experimental mRNA vaccine co-developed by biotechnology company Moderna and National Institute of Allergy and Infectious Diseases (NIAID) was injected into a volunteer just two months after the publication of SARS-CoV-2’s genetic sequence.
The vaccine candidate, as well as the one developed by BioNTech, moved into phase 3 studies in July the same year, marking a major milestone.
It was a moment of glory for these researchers when the mRNA vaccines successfully secured the first two emergency use authorisations from the world’s top regulators known for their stringency. Amazingly, these two candidates won consecutive regulatory clearances within a matter of weeks, leaving behind front-runners from the likes of Oxford-AstraZeneca, Johnson & Johnson and Sanofi-GSK, as well as thousands of scientists around the world, both from the academia and the industry, who were burning the midnight oil to develop a vaccine.
Meanwhile, Oxford and AstraZeneca came up with muddled results using two different doses in clinical trials in Britain and Brazil. In a two full dose regimen, the efficacy was 62 percent, whereas, in the one full and a half dosing, they came out with data showing 90 percent efficacy. Towards the end of December,however, UK MHRA granted an emergency use authorisation to the vaccine.
Sanofi and GSK found data from their adjuvanted vaccine disappointing in early clinical trials as the vaccine failed to reproduce the promising immune response in the elderly. Subsequently, the world’s vaccine behemoths announced a delay in their vaccine programmes as they announced plans to trial a new version.
Pfizer and Moderna: Similar yet different
The results from Moderna and Pfizer vaccines were “extraordinarily comparable”, say experts. Both vaccines are similar in their ingredients, but not identical. Both consist of mRNA genetic material. However, the two companies use different types of fat molecules to encase mRNA.
There are other characteristics that make them unique in their own ways. For example, Moderna’s vaccine requires considerably less cooling for storage and transportation than Pfizer-BioNTech’s product.
Efficacy in elderly: Data from the Moderna vaccine showed a comparable level of efficacy across different racial and ethnic population groups such as Whites, Blacks and Hispanic volunteers, men and women, healthy participants and those at risk of severe COVID-19 with co-morbidities like obesity and diabetes who participated in the trials.
In people aged 65 and older, the Moderna vaccine demonstrated 86.4 percent efficacy. Even though it is lower than 94% overall efficacy shown by the vaccine, the level is considered “fairly good” by experts.
While announcing the interim data, Pfizer had said earlier in November that a vaccine efficacy rate of over 94% was observed in adults over 65 years of age.
Epidemiologists consider it critical to immunise the most vulnerable groups on priority during a pandemic.
Besides their effectiveness on the elderly, the experts were equally keen to know how the candidate vaccines were useful in asymptomatic cases—a hallmark of SARS-CoV-2 infection; the potential of the vaccine to stall severe illness, the duration of protection offered after inoculation etc.
Addressing severe infection: The benefits of preventing severe COVID-19 is tremendous because such cases often lead to hospitalisation and an increase in fatality counts. On this front, Moderna produced more evidence. Of the 30 volunteers who developed severe cases of COVID-19 during the trials, all had received the placebo, not the vaccine.
The Pfizer-BioNTech findings reported ten severe cases in the placebo group and one in the vaccinated group. Of course, these numbers are too small and only provide an indication and cannot be taken as conclusive findings for the vaccine’s ability to prevent serious illness.
Prevention of asymptomatic transmission: Another lingering question is whether the vaccine is capable of fighting asymptomatic infections. A vaccine that could do that could be key to shaping the course of the pandemic, because COVID-19 researchers say that SARS-CoV-2 infected people with no symptoms are a major source of transmission.
It has been found that a vaccine that prevents illness might still allow people to become infected and harbour the virus in their nostrils long enough to transmit it.
Moderna data suggest that its vaccine may reduce the transmission of the virus from a recovered patient’s nose. Those people who had one shot were less likely than those in the placebo group to have symptom-free infections in their noses. They are therefore less likely to spread the disease to others.
Pfizer is now studying the effectiveness of its COVID-19 vaccine in asymptomatic cases, reports said, quoting Kathrin Jansen, head of vaccine research and senior vice president, Pfizer. The results could be known in early 2021, according to her.
Duration of protection: Another important difference found was that the Pfizer-BioNTech vaccine took effect and started protecting against the virus within about 10 days of the first dose. Noticeably, such an effect after the first dose has not been reported by Moderna. However, two doses of the vaccine were found essential for full protection in both cases.
Despite the high efficacy demonstrated by these vaccines, vaccine experts don’t have a good understanding of exactly how long a COVID-19 vaccine might protect an individual from infection. According to data published as a letter to the editor in New England Journal of Medicine, three months after getting their second dose of Moderna vaccine, 34 healthy adults still had relatively high levels of neutralising antibodies. Antibody levels did decline a little in the elderly, but overall, researchers said the results were encouraging.
“These data give us further optimism to expect that the high level of efficacy recently demonstrated by mRNA-1273 to prevent COVID-19 disease will be durable,” Dr Tal Zaks, chief medical officer of Moderna, said in a press release.
In children and pregnant women: One of the remaining points of uncertainty is exactly what levels are needed to maintain functional immunity. This is unlikely to be settled any time soon, as only time can tell whether booster shots will be required. Similarly, there is no data available as to how these vaccines work on children and pregnant women. The Pfizer-BioNTech vaccine was authorised for people as young as 16. At the same time, Moderna has studied the vaccine in people 18 and older. Both companies are running trials on children as young as 12 and have plans to start studying even younger children, reports said.
The superior edge
Unlike viral vector vaccines which employ engineered human cold viruses, the mRNA approach has nucleic acids encapsulated in a nanoparticle carrier. mRNA vaccines can also be made faster as they don’t have to be grown in eggs and cells, a time-consuming and costly process. These vaccines are simply chemicals catalysed in a test tube or a tank. This provides them an edge over conventional approaches.
Immunologically, genetic vaccines recruit CD8+ cytotoxic T cells, also known as killer T cells, through the major histocompatibility complex class I pathway, in addition to eliciting antibodies and CD4+ helper T cells.
This is considered a major advantage in comparison to conventional vaccines where only just a protein or a dead virus is injected and they don’t stimulate the T-cells.
RNA vaccines also possess unique merits even within genetic vaccines as well. Many vector-based vaccines employ engineered human cold viruses to deliver the relevant genetic sequences into the cells (The Oxford vaccine candidate ChAdOx1 nCoV-19 is an aberration as it uses an adenovirus that causes cold in chimps). This can encounter pre-existing immunity in some geographical regions, rendering the vectored vaccine less effective. Pre-existing immunity to self-replicating viral vectors may be the reason why CanSino Bio’s potential COVID-19 candidate flunked in phase 1 studies and failed to elicit the expected level of neutralising antibodies.
Pre-existing neutralising antibodies to human adenovirus 5, known as Ad5, ranges from up to 69% in the US to 80% in Africa, studies show. Cross-reacting pre-existing immunity to human adenoviruses could diminish the response in non-human vectors too.
Researchers also point to the fact that RNA- vaccines are more efficient than their DNA counterparts because 95% of the cells that meet the RNA take it up and make protein, unlike the latter which first have to enter the nucleus to make mRNAs to produce the protein. This rather convoluted process can reduce the efficiency of DNA vaccines. mRNA is an intrinsically safe vaccine as it is only a minimal and transient carrier of information that doesn’t interact with the genome.
With inoculations using mRNA vaccines getting kick-started in many regions of the world, the spotlight is now turned on to their safety and long-term efficacy. As indicated, mRNA vaccines are desperately lacking in clinical data. Though relatively new, non-replicating adenoviral vector vaccines have at least some real world data around them.
One of the vaccines produced by Janssen against the Ebola virus using the adenovirus vector platform was authorised in the EU in July.
Studies on other potential mRNA vaccines are underway against rabies, Zika, influenza etc. No major severe adverse events have been reported, so far.
Despite a higher degree of efficacy and a favourable safety profile of mRNA vaccines scientists are keeping their fingers crossed as unexpected adverse effects could emerge later.
Several countries have already reported cases of reinfection by SARS-CoV-2 within weeks and months of discharge from the hospital. Studies say that the rapid decline of antibodies after recovery could be the cause of reinfections. Researchers, however, say that 2-dose regimens could help to overcome this.
Re-infection or re-emergence can also be caused by a different strain of the virus, which can also render vaccines useless. RNA vaccine makers, however, look highly confident on this front.
One of the key features of the mRNA technology is that the vaccine can be upgraded according to new mutations in the pathogen. Technically, it will take only 6 weeks to prepare the vaccine for a new strain like the one found in the UK, Sahin revealed in a virtual press conference recently.
Safety of ‘a minimal genetic construct’
Even though mRNA vaccines have been shown to be safe and reasonably well tolerated in several phase 1 and phase 2 studies, recent human trials have demonstrated moderate, and in rare cases, severe injection site or systemic reactions for different mRNA platforms. These include local and systemic inflammation, the biodistribution and persistence of expressed immunogen, stimulation of auto-reactive antibodies and the potential toxic effects of any non-native nucleotides and delivery system components.
It has also been observed that some mRNA-based vaccine platforms induce potent type I interferon responses, which have been associated not only with inflammation but also potentially with autoimmunity. So, it is better to identify individuals at an increased risk of autoimmune reactions before mRNA vaccination.
The presence of extracellular RNA during mRNA vaccination is another concern. Extracellular naked RNA has been shown to increase the permeability of tightly packed endothelial cells and may thus contribute to oedema. Extracellular RNA has also been found to promote blood coagulation and pathological thrombus formation.
The official guidance says there are no safety concerns about giving the currently authorised vaccines to people. After reviewing the data submitted by Pfizer/BioNTech and Moderna, the USFDA said the vaccine trials show that side effects are common, though there are “no specific safety concerns identified that would preclude the issuance of an emergency use authorisation”. mRNA is a minimal genetic construct. It harbours only the elements directly required for production of the protein and doesn’t interact with the genome. This way, a potentially detrimental genomic interaction is excluded. Being non-replicative, mRNA decays within a few days.
The vaccine also seems to be safe, according to the trials. The most common side effects reported were headache, fatigue, myalgia, chills, and injection-site pain. Moderate local and systemic reactogenicity events were reported after the administration of the second dose of the vaccine.
There were four cases of Bell’s palsy among those who received the Pfizer vaccine. This includes one in a person with a history of the disorder. No case was reported in the placebo group.
Moderna said three participants in the vaccine group and one unvaccinated (from the placebo group) developed the temporary facial paralysis.
Viral infections could trigger Bell’s palsy. But the FDA could not definitively link the incidents to the vaccine. So far, no link has been established between the disorder and any vaccine routinely recommended. However, the US FDA said the agency would recommend tracking Bell’s palsy cases as the vaccines roll out.
“Vaccine effects are so rare, you need a massive and very powerful epidemiological study to show that there actually is an association with the vaccine, ” the agency said.
Nevertheless, on the first day of administering Pfizer’s vaccine to older adults in care homes and to front-line healthcare workers in the UK, two recipients with a history of severe allergic reactions, called anaphylaxis, experienced reactions after getting the vaccine. Following this, the NHS issued a directory alerting that people with a history of significant allergic reactions should not have the Pfizer/BioNTech COVID vaccine. Sporadic incidences of anaphylactic reactions were reported with both the vaccines in other places as well.
In the Moderna trial, nearly 9.1% of the volunteers in the late-stage studies had injection-site reactions that the FDA considers severe or medically significant. In comparison, fewer than 1% of placebo recipients had these kinds of serious reactions.
The FDA also found among vaccine recipients a higher rate of certain allergic reactions than those who received a placebo.
This shows that the proof of the pudding is in the eating and side-effects can emerge when a vaccine is moved outside carefully controlled clinical trials.