In April, the world had marvelled at the bravery of Dr Elisa Granto, a young biologist of the Oxford University. Reason? Granto was seen receiving the experimental vaccine being developed by a collaborative effort between Oxford University and the multinational company AstraZeneca. Granto certainly deserved praise, but she was not the only one; she was part of a team of 1077 volunteers who have contributed to the Phase1/2 trials of the ChAdOx1 nCoV2019 vaccine. The success of these experiments was announced by the team of Oxford/AstraZeneca scientists in their research article published in the prestigious journal The Lancet on July 20. The global enthusiasm regarding this much-anticipated news was not unexpected.
However, what got somehow lost was the fact that another group of scientists had published similar results from similar trials in the same issue of The Lancet. This experimental vaccine, from the Chinese company Cansino Biologics in collaboration with the Academy of military medical sciences, has also now crossed the phase 2 trials successfully. Taken together, this is a milestone in humanity’s battle against the latest pandemic.
Both trials had two major objectives. Firstly, to assess whether the vaccines could induce an useful level of specific anti-SARS-CoV-2 immune response in the volunteers. Secondly, it was essential to see whether the vaccination resulted in nasty side-effects.
A brief overview of the vaccines before we proceed further. The traditional way of making vaccines has been to prepare inactivated or weakened pathogens or specific cellular components of the pathogens (proteins/carbohydrates) and inject them. This is ‘noted and remembered’ by the immune system and if the real pathogen (virus/bacteria) enters the body sometime in the future, the immune system is primed to recognize it and marshal its forces quickly to search and destroy the germ before it causes disease.
Advances in genetic engineering have allowed development of a different type of vaccines. Both the Oxford/AstraZeneca and Cansino vaccines are made of modified Adenoviruses. Several Adenoviruses cause relatively harmless infections in man and other animals; The Oxford vaccine is built on an adenovirus taken from chimpanzees, while the Cansino vaccine is based on a human adenovirus Ad5 (which has been earlier used for gene therapy). The viral genetic circuits have been tweaked and the gene for SARS-CoV-2’s spike protein has been inserted. This has resulted in an engineered viral vector which cannot multiply and cause disease when injected into the human body but has the spike protein from the novel coronavirus. The vaccine developers hoped that the presence of this spike protein would induce a specific strong and safe immune response in the volunteers.
The Oxford/AstraZeneca vaccine had been initially checked in Rheseus monkeys. The success of those pre-clinical trials prompted the combined phase 1/2 trials in human volunteers in five hospital centers in Oxford, London, Bristol, Southampton and Weston. The research article reports that a total of 1077 volunteers, aged between 18 and 55 (average age: 35 years) were vaccinated. The trial had similar number of men and women and all were ‘whites’.
543 volunteers received one dose of the trial vaccine. 10 of them received a second booster dose 28 days after the first vaccination. The remaining 534 volunteers were injected with an in-use Meningococcus vaccine. This group of 534 is what is called a ‘control group’ and comparing the physiological and immune responses of the experimental group with the control group is fundamental to understanding the effects of the new vaccine.
Thousands of miles away, in the Chinese province of Wuhan, over 500 volunteers (aged18 and above, and with no history of infection during covid-19) were divided into three groups. The first group of 253 volunteers received a low dose of the Cansino vaccine. The second group of 129 volunteers received a higher dose, and the 3rd group of 126 men and women were injected with a placebo.
On several days over the next two months, the English and Chinese volunteers were repeatedly tested to see whether the vaccines induced antibody production and T cell activation. Importantly, the published results show there are no serious side effects. Many volunteers have complained of body ache, malaise and headaches and some Chinese volunteers who received the higher dose reported fever. But, all recovered on their own or with simple treatment with Paracetamol. The safety objective of the trials had been achieved.
ELISA and other tests showed that good levels of anti- SARS-CoV-2 IgG antibodies were detected in all volunteers. And in Oxford/AstraZeneca volunteers, who got the booster dose, the antibody titre rose to ~5 times of the ones who got the single shot.
Notably, both groups have drawn focus towards the fact that the vaccines can activate T lymphocytes, the big players of the cell-mediated immune system. Less known to the general public compared to antibodies, T- lymphocytes (also called T-cells) are the onfield commanders of the body’s immune mechanisms and their importance is second to none. An immune system without T cells is practically a car without a driver. Moreover, cell-mediated immunity is a key antiviral combatant. The success of both Oxford/AstraZeneca and Cansino vaccines is that both activate T cells. Combined with the rising levels of antibodies, this means that both arms of the immune system are induced by the vaccines. This is big undeniable success.
A notable point, mentioned by the Cansino group, is that volunteers who had been infected by some Adenovirus earlier show a lower antibody level when this vaccine was injected. It is likely that the body recognized the vaccine as an incoming adenovirus and destroyed part of it – a same-side goal that partly blunted the desired immune response. This is important because adenoviruses are not-uncommon human pathogens and have caused mild diseases (cough, cold, fever, stomach upset, etc) in many people. The efficacy of the vaccine need to be tested in this context.
What’s next? Both vaccines now proceed to phase III trials. Both groups have clearly written that the numbers tested is significant but too small. Restricting tests only to whites and Chinese will not suffice. The efficacy of the vaccines must be tested on people of different communities and nations, people of different age groups and men and women already suffering from some diseases. If successful and safe, children will be injected with the vaccines for further tests. Importantly, neither vaccine has been tested by exposing volunteers to the actual SARS-CoV-2 pathogen. Of course, such ‘challenger’ trials need special rules as well as a lot of ethical considerations before being done.
For the Oxford/AstraZeneca vaccine, it is known that the next trials are already underway in Britain, Brazil and South Africa. Since the Chinese military establishment has already put the Cansino vaccine on a priority, it is not surprising that they will be doing the same. It is likely that some stocks of both vaccines will be ready by the end of the year (Indians can carry some extra hope on the Oxford/AstraZeneca vaccine as Pune’s Serum Institute of India is their collaborator). However, mass production and delivery for entire populations is unlikely before 2021. That is okay – science is not about bombastic proclamations and dramatic strides, it is mainly about incremental progress. Good to hurry but not at the expense of safety. Better safe than sorry.
–Anirban Mitra,
Teacher of molecular biology and biotechnology, based in Calcutta
References: THE LANCET
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