The quest for a vaccine to arrest the novel coronavirus pandemic reached a new height with two vaccines, one from the Astra Zeneca, UK and another from the CanSino Biologics, China, showing promising results. It must be pointed out that last month the live attenuated virus containing Coronovac from Sinovac similarly completed phase trials and moved into the Phase 3 trials.
Using genetically engineered common cold adenovirus as a vector, both the groups present the antigen of SARS-CoV-2 spike glycoprotein receptor binding domain to elicit the immune response. Both the vaccines show successful production of antibodies by B cells and also T cell response to the novel coronavirus. If successful in phase 3 trials, these will be the first-ever adenovirus vector-based COVID-19 vaccine for humans.
The antigens are parts of pathogen with a specific molecular structure. In the case of the novel coronavirus, the receptor-binding domain on its spike protein ‘fit’ the ACE2 receptor on the surface of the human respiratory cells to gain a foothold. So the spike protein is a prime candidate for having exposed antigens that can raise B cell antibody response. The B cells of the human immune system secretes molecules called ‘antibodies’ that bind with complementarity to the antigenic part of the pathogen and may prevent it from infecting, in which case it neutralises the pathogen. One can imagine the antigen present on the surface of the germs as ‘nuts’ and the antibodies as appropriate spanners which can grip and unfasten the particular ‘nut’. That is, the antibodies are tailor-made to each antigen of a pathogen, in this case a virus.
Pieces of virus antigens are often presented as part of the immune system response on the surface of an infected cell. Like a police dog trained to sniff out hidden narcotics, the T cells, a type of white blood cell, can smell the infected cells that have been turned into veritable virus-making factories. Like a dog trained to identify a snake in the field by a farmer is often ineffective in locating explosives, a T cell which has a different receptor is ineffective against another pathogen. T cells have receptors on its surface that can bind only with one shape of a T cell antigen, like a lock and its key. Helped by the antibody, new T cells with appropriate receptors for the T cell antigen are forged by the immune system. Cytotoxins, a kind of toxin, is released when a T-cell receptor fits with its viral antigen, killing the infected cell. Apoptosis, or cell death, of infected cells prevent the release of new viral particles and thereby, reduces the potential for bystander cells to become infected.
Once bitten twice shy
Generation of neutralising antibodies and T cell responses are the two most important immune response to an infection. With the secretion of neutralising antibody, the contagion, which is the viral entry into a cell, is interrupted. With the T cell targeting the infected cell, the spread of the infection is blocked. The infected patient overcomes the pathogen and becomes cured.
Once a viral infection is cleared, the immune responses are not forgotten. The B cells that produce the antibodies against exposed viral antigens and the T cells that recognise infected cells forge memory B cells and memory T cells. When the same germ attack next time, the memory B cells and memory T cells are able to produce the necessary immune response swiftly. The pathogen is cleared in no time. The person does not get sick. This is called immunological memory. That is we acquire immunity against that particular pathogen after contracting the disease first time. Vaccination is a technique to artificially induce the immune response to a dangerous pathogen to acquire immunity without getting the disease. In some cases, the immunity, once acquired, serves lifelong. In some cases, the immunity lasts only for a duration.
Adenovirus vector vaccine
The challenge for vaccination is presenting the viral antigen without causing threatening infection. How about using a tame, lame virus to take the antigen of a virulent pathogen? This is the idea behind the adenovirus vector vaccine platform.
Adenovirus is a family of virus that infect humans and animals. Most of the adenovirus that infects animals cannot replicate inside human cells. Those that affect humans are tame as a lamb, at the best they cause mild cold.
Just as a feature film is made by editing individual scenes shot separately, the genome sequence coding the antigen part of a life-threatening virus can be spliced and joined with the harmless adenovirus genome.
The vaccine by AstraZeneca & Jenner Institute at Oxford University, UK, ChAdOx1 nCoV-19 uses the adenovirus that infects the chimpanzee and the one being developed by the scientists led by the Beijing Institute of Biotechnology & CanSino Biologics in Wuhan, China uses the non-replicating Human Adenovirus 5 (Ad5). Both these adenoviral-vector shuttles a gene from novel coronavirus into our bodies where our cells will read it and make coronavirus spike proteins. With the viral proteins produced inside our cells, the vaccine mimics the events in a natural infection. Our immune system is tricked into believing that the body is infected. The immune response is unleashed; neutralising antibodies are produced. This activates the T cells of our immune system to attack these vaccinated cells. In the process, T cells are trained to seek and destroy cells infected with the real virus in the future. Immunity is acquired.
Encouraging results from human trials
The Oxford vaccine was tested among 1,077 healthy adults aged between 18 to 55 years. In the double-blind control trial, randomly individual volunteers were chosen to be administered the ChAdOx1 nCoV-19 vaccine formulation. In contrast, the control group were given the meningococcalvaccine. The reaction and the immune response of the vaccine among the volunteers were observed. The study showed that the neutralising antibodies produced by B cells were generated in more than 90 per cent of participants. T-cell reactions were induced in all participants.
Further, the immune response was sustained up to 56 days of observation. When a small group were given a second-dose booster, they showed much stronger neutralising immune responses. To speed wrap the development, the human clinical trial phase 1, which usually ensure the safety, and the human clinical trial phase 2, which look for immune response and dosage, were combined into a single overlapping trial.
In the case of the Chinese vaccine, human clinical trial phase 1 was completed way back in March 2020 with the participation of 108 volunteers. The study showed that Ad5 vectored COVID-19 vaccine was tolerable and immunogenic at 28 days post vaccination. In the human clinical trial phase 2, vaccine formulation at two concentrations were tested against a control placebo among 508 healthy volunteers aged between 18 to 83 years. Neutralising antibodies were generated in about 85 per cent cases. More than 90 per cent had T-cell responses, demonstrating that the Chinese vaccine produced robust immune responses.
“Caution is the eldest child of wisdom,” famously said Victor Hugo. The research on the adenovirus vector platform for the vaccine is at least three decades old, so far, and there are many vaccines using this technology under different clinical trial phases. But as yet, there is no adenoviral vector vaccine for use among humans. Only one adenoviral vector commercial vaccine, a rabies vaccine used to immunise wild animals, is in the market. So far, the results from the two vaccines have been encouraging. Despite the differences in the adenoviral vectors used and the geographical locations of the study, overall, the results of both trials are broadly similar.
Now, both these vaccines have to be tested on a more significant number of participants with different profiles to assess their efficacy and safety in the phase 3 trials. Is a single dose sufficient for older adults? If two doses are given, does the immune response longevity sustain for much longer? Are there significant host-specific differences in immunogenicity by age, sex or ethnicity? Is it safe for pregnant women and children? These are some of the pertinent questions one needs to address in the large scale randomised double blind phase 3 trials.