Vaccines: One stop solution for COVID-19

Disclaimer: Author is neither an expert in virology nor vaccines. But once in a while attempts to simplify Science so that it can find a place among dinner table conversations.

In the nearly 300 year long history of vaccines against infectious diseases in humans, vaccines against SARS-CoV-2 together stand as a tall beacon of light. The identification of the pathogen (germ) causing the infectious disease, deciphering it's genetic material, understanding it's proteins and developing of vaccines, all happened within a span of months. Clinical trials for vaccines in healthcare workers were started soon after. And within a year of COVID-19 being announced a pandemic, the world was looking at vaccines against this submicroscopic agent of ghastly change. The accelerated development of COVID-19 vaccines is a culmination of prior years-long efforts of research on coronaviruses, vaccine research and advanced technology development. COVID vaccines aren't magic remedies, but one of the first expedited outcomes of the scientific investment humankind has made. Not to mention the cordial research that happened beyond boundaries of nations, and scientists who worked 24x7 across the globe until they could figure out this new foe.

What is a vaccine? Simply put, it is a dummy version of the disease-causing pathogen that will let our immune systems develop a defense and a memory of that defense such that when the actual infection occurs, the body is primed and ready to fight off the infection. In 1796 Edward Jenner first tested the effectiveness of a smallpox vaccine- a pus like material from cowpox inflicted individuals. Ever since then scientists have developed 40 plus preventive vaccines and millions of lives have been saved year after year.

Every child born in India is recommended to take the BCG (Against Tuberculosis), HBV (Against Hepatitis B) and OPV (Against Polio) vaccines as early as the time of birth. The Indian Academy of Pediatrics recommends 20 vaccines spaced out within the ages of 0-18 years. These vaccinations have saved millions of Indian lives over the years, which would have been otherwise lost to infectious diseases. The fundamental basis of a vaccine is this: introduce the immune system to some components of a germ causing the disease, which the body would recognize as 'foreign' and will prepare to attack. Through the introduction of a vaccine into the body, the immune system learns how to fight against the germ and in the process develop a 'memory'. This priming of the immune system allows the body to mount a strong immune response during the event of an actual infection, reducing the damage caused by the disease, and most importantly, mortality.

 
Few months into the first COVID-19 wave, experts had predicted that vaccinations are going to be the ultimate defense against the SARS-CoV-2. Anti-viral drugs have largely remained elusive and even the early drug trials such as the SOLIDARITY and RECOVERY could not identify any strong contenders for decimating the virus or improving the progress of the infection. Few months into the pandemic it was also very clear that naturally induced immunity by the virus is not long lasting and wanes beyond 6-7 months, leading to re-infections. Till date fourteen vaccines against COVID-19 have been approved for use, six of them WHO approved. These fourteen vaccines are majorly of four types: Inactivated virus vaccines, RNA vaccines, viral vector vaccines and Protein subunit vaccines.

 
Like mentioned before, vaccines are dummy pathogens (germs). Inactivated virus vaccines usually contain a dead version of the pathogen, which is unable to multiply and infect a person. But the small amount of the dead virus is enough to train the body on how to fight the actual virus. RNA is a biochemical molecule present in all living beings. It is a script which contains the information on how to make proteins, which constitute individual units of life; for instance in larger animals a single unit of life is a cell. RNA vaccines contain the info to make a protein of the SARS-CoV-2 virus, the spike protein, which acts like a key and helps the virus attach to human cells during infection. The introduction of only the spike protein is enough to alert our immune systems, which will start producing fighter molecules called 'antibodies' (This is what is measured in antibody tests for COVID-19. If you possess antibodies against COVID-19, it means your body has mounted an immune response against the virus, through infection or vaccination). Viral vector vaccines use a packaging of another virus to deliver parts of the actual pathogen into human cells. These viruses can enter human cells, cannot divide, but can make proteins of the virus we want to develop immunity against. This helps some immune cells to be alerted of a threat and thus induce immunity without any infection. Protein subunit vaccines only introduce some viral proteins or even parts of a protein that will be detected as an 'antigen' or foreign material and the body will produce antibodies against these antigens. Note that none of these vaccines themselves can multiply within the human body and hence cannot cause an infection.

As of May 2021, nearly 180 vaccines are in pre-clinical development and around 90 in clinical development. The developmental stage of every vaccine involves pre-clinical and clinical studies. The preclinical stage involves experiments not done in humans. During this stage the vaccine is introduced into "model systems" which mimic a human body. These are sometimes animals like mice, rabbits or guinea pigs or sometimes 'cultured' human cells. It is possible to grow human cells in petri dishes and flasks in a conducive environment. Such an alternative model system of human cells reduces harm to animal model systems. If the vaccine does not cause any extreme effects in a cultured cell or animal model system, it can move into the clinical trial stage. The clinical trial stage which happens in human subjects has three phases. During the first phase the vaccine is tested in a very small group of human volunteers, to mainly understand if there are any damaging effects from the vaccine. During phase II, a higher number of volunteers are recruited from a target group for the vaccine, few hundreds in number. Phase II clinical trials assess efficacy (see next section) and check for safety. For example the initial COVID-19 vaccine trials were held only in adults, not in teenagers or children. So these vaccines were at first only approved for the adult populations, once they cleared phase III trials. Phase III trials are performed in volunteers in the target group in hundreds to few thousands, during which effectiveness (see next section) and safety of the vaccine is confirmed. Additionally, phase IV trials may be conducted after the vaccinations are done, over a period of time, to assess long term immunity and other effects induced by the vaccines. Vaccines that cross phase III trials then go into licensure phase and deployment, based on regulatory policies of individual nations.

Efficacy and effectiveness of a vaccine
Imagine someone taking a driving test. They might have been riding a vehicle and mastered driving slowly. An instructor might have probably deemed them ready to take the test. In India, they first take a 'learners' test' to check if they know the traffic rules. Then during the driving test they are told to drive in a particular set of patterns (like an 8 for two wheelers or H for four wheelers) and probably drive through a road with minimal traffic. The ones who cannot perform in these 'monitored' conditions are asked to retake the test or are simply failed. Once the person gets a license, they may go on to a crowded road, but now they are faced with much more traffic, with maybe even some unruly drivers dashing past or towards them. Once in a while in spite of knowing the traffic rules by heart and having practised for days, accidents may happen. Minor or even major. But on an average, one would assume that a person with a license can drive responsibly on the roads with minimal or no damage.

Vaccines, with their trials, licensure and deployment is more or less like an amateur driver getting licensed and meeting the real traffic, or the real world. If a pre-clinical trial is like a learners' test, a driving test would be like a clinical trial. During a clinical trial if a vaccine proves to be immunogenic, that is, it can induce enough immune response, and does not cause any major safety issues, it is called an efficacious vaccine. For example, Moderna’s COVID-19 vaccine has 94.5% efficacy and Pfizer’s 90% efficacy. This means that in a controlled study of volunteers with recorded medical statuses, Moderna's vaccine showed protection in nearly 94.5% volunteers, while Pfizer's vaccine shows protection in 90% volunteers. Phase III clinical trials give a glimpse of how well the vaccine will perform in the real world, because more the number of participants in the study, more the random chances of finding someone who may not develop immunity or contrarily, develops side effects. This is like the drive through on a road on the day of the driving test; the examiner can still call off the license if something seems off.

How well a vaccine performs in the real world is called effectiveness, and may not be as high as a vaccine's efficacy. The effectiveness of a vaccine is determined by continuous surveillance of people undergoing vaccinations. In short, if experts (in this case epidemiologists) were to compare two groups of people from the same population, the ones who got the vaccination, and the others who did not, and see which group had a higher chance of getting an actual infection, they can understand the effectiveness of a vaccine. This is also like driving on a full lane of vehicles with drivers with varying driving styles: the vaccines may encounter people who are extremely sensitive and develop allergies or even people who do not develop any immunity at all (such individuals are called immunocompromised). In the case of Astra-Zeneca (Covishield) COVID-19 vaccine, a very small portion of vaccinated individuals developed blood clots- a chance much lower than taking other medications, and more importantly, many magnitudes lower than when getting infected by COVID-19. Effectiveness of a vaccine can only be determined retrospectively, when a large portion of the population has been vaccinated and challenged by the actual pathogen, here point in case, SARS-CoV-2. All in all, till date it has been shown that the safety of COVID-19 vaccines and their effectiveness far outweigh any side effects or adverse events.

Breakthrough infections
The protection of a vaccination can be measured on a vast scale, just like accidents on the road are. When the COVID-19 vaccinations were rolled out, experts were eager to see what level of protection they could give against infection, severe disease and death. Will they protect a person with absolutely no trace of infection or will they cause mild symptoms? What percentage, predictably low, will show severe symptoms and may lead to mortality? From the several months that the vaccinations have been progressing around the world, we know that most COVID-19 vaccines provide a very high protection against severe symptoms, after full vaccination, that is after two doses of the vaccine. However, there have also been reports that some individuals developed symptoms even after full vaccination, called breakthrough infections. India has been vaccinating individuals, starting with healthcare workers since January 2021. Till now few reports of breakthrough infections have been reported, a majority of them with mild symptoms and no requirement of hospitalization. 

There have also been standalone news reports on breakthrough infections leading to severe symptoms and sometimes deaths in India. Studies are being undertaken to understand why these infections are occurring. A look at the effectiveness data of many COVID-19 vaccines have shown high effectiveness against severe disease after two doses. Sadly, breakthrough infections and severe outcomes are inevitable when the number of active cases are high- remember that 90% of 10 is 9, of 100 is 90, of 1000 is 900, and so on. Which means even if our vaccines were 90% effective, in a country of 1.3 billion, we will get to see some people who may not develop enough immunity to throw off the infection completely. This does not imply that the vaccines are not working, this simply means that the number of cases are high and the good news is that most of the vaccinated individuals are well protected. More encouragingly, vaccines have been shown to be effective even against variants of concern of SARS-CoV-2 with properties of high transmissibility and immune evasion, with both doses of the vaccines. But the more the virus remains in circulation, the higher the chance of the evolution of immune escape variants, and the only way to combat it is to vaccinate as rapidly as possible, so that we reduce the spread.

Vaccines work
As emphasized before, the fact that we are seeing breakthrough infections in no way implies that vaccines don't work. The vast majority of people who are infected are protected from severe disease. But the genomic surveillance of the virus variants that cause breakthrough infections can help us understand viral evolution and lead to better designing of vaccines. Real world data has shown us that two doses of vaccinations, for vaccines across the table, have been effective enough. As of now, Pfizer has announced the need for a booster dose after a year of the first two doses. AstraZeneca also recently tested a third booster dose. Almost like an instant effect of widespread vaccination is the drop in number of deaths, followed by drop in positivity rate, as clearly seen in both Israel and the UK. The US and Canada have also witnessed the effectiveness of vaccines in bringing down numbers, even with highly transmissible variants circulating in the population. India recently has concluded a drop in COVID-19 induced mortality in the age group of 60 plus owing to vaccinations. Apart from the protective effect of vaccines, there is also evidence now that vaccines improve symptoms in long haulers of COVID. Since last year there has been growing evidence that the recovery from COVID is not a black and white scenario, but many people sustain post- infection effects for many months. Vaccine mediated immune system activation that helps long COVID patients recover is thus an additional benefit of vaccination. What's more, combinations of vaccines of different types are also in clinical trials, which may help us have more effective vaccines soon, even against virus variants. The bottom line is: vaccines work. Get your shots, as and when they become available.

 
Naturally the discussion then moves to the availability of vaccines. As early as the end of 2020, it was predicted that lower and middle income countries (LMICs) might have access to vaccines only probably by 2022. The economic disparities coupled with lack of logistics to handle cold storage vaccines were slated to hamper vaccine procurement and distribution by LMICs. India has approved three vaccines till date for distribution: the indigenously developed Covaxin by Bharat Biotech and ICMR, Covishield which is an Indian version of the Oxford-AstraZeneca and the latest, Sputnik V from Russia. In the current roll out, India has used both Covaxin and Covishield vaccines. Although the app-based distribution has not be very smooth until now, in the coming months it is expected that our vaccine demands will be met.

Finally, is it enough to be vaccinated? The chances of breakthrough infections and the evolution of immune escape variants of SARS-CoV-2 mean that we will have to continue with COVID precautions even after full vaccination, until further notification from experts. Controversial decisions on mask wearing have been made in some countries, but for India the writing on the wall is clear: we are a billion-strong country, we cannot take chances, even with highly effective vaccines. The ferocity of the second wave of COVID-19 in India has had millions scrambling for access to healthcare, and many lives have been lost for a variety of reasons. We should continue to follow the COVID etiquette, until the worst has passed. Remember, the vaccines will definitely save us, but no one is safe, until everyone is safe.