Why safety comes first for vaccine development in Bangladesh

The mainstream print media and online portals have been buzzing with news of Covid-19 vaccines and its development recently. But the question arises, does Bangladesh have the capability to develop a vaccine? 

To answer this, it is necessary to shed light on the competency of our pharmaceutical industries. 

Based on our experiences in academia, research, and relevant biopharmaceutical industry for almost 20 years at home and abroad, we wish to share our opinion about the current vaccine or biotech drugs development capabilities in Bangladesh.

The rise of pharmaceutical industries in Bangladesh  

In the last 30 years, the pharmaceutical industry in the country has made remarkable progress in the production of generic drugs (i.e., copies of medicines made by the original drug manufacturers).

After meeting 98 percent of the local demand, these drugs are being exported to over 130 countries around the world, earning around $130 million every year. 

At the heart of this achievement lies the challenging initiatives of the owners of the pharmaceutical industries along with the necessary support from the Directorate General of Drug Administration (DGDA). 

Medicines are not like usual consumer goods so it is very important to ensure its quality. 

To ensure the quality of medicines, the regulatory department of drug administration investigates the production plant, Quality Control (QC), and Quality Assurance (QA) departments in the pharmaceutical industries to ensure the pharma companies strictly follow the proper and specific rules and regulations. 

DGDA provides marketing authorisation of drugs only to those pharma companies that pass the quality evaluations of DGDA. It is worth noting that exporting generic drugs abroad, particularly to the USA and Europe, is often challenging due to the regulatory hurdles of those countries. 

The silver lining is that Bangladesh has gained tremendous expertise in the field of generic drugs (establishment of industry, skilled manpower, regulatory issues) in the last three decades.

Is Bangladesh capable of making raw materials for conventional generic drugs?

Despite considerable progress in the country's pharmaceutical industry, Bangladesh has yet to achieve the capability to manufacture raw material API (active pharmaceutical ingredient) for developing drugs, which we are still importing from other countries. 

Only the formulations and packaging of these medicines are done in Bangladesh. If the capacity to produce raw materials is not achieved by 2033, the entire sector may be threatened. 

Being a developing country, Bangladesh has so far been exempted from the patent issue of major pharmaceutical companies. 

Making raw materials for generic drugs requires a lot of skills, investment, and experience, which pharmaceutical industries in Bangladesh are yet to achieve.

Only a handful of companies are trying to build API capabilities. It is hoped that by 2033 some companies will be successful.

The comparative technical complexity of generic and biotech drugs (e.g. insulin) 

Generic drugs (small molecules, such as paracetamol, antibiotics) are made by the API chemical process. On the other hand, biotech drugs (large molecules) or biologics (such as insulin) are made through biological processes. 

Chemical drug synthesis is relatively easy to control and batch variations are often low. On the other hand, controlling the biological system is a very difficult and daunting task where a small variation in the process usually has detrimental impacts.  

Therefore, strong scientific and technical skills in the biomedical field are required with huge investments to ensure the quality of biologics. That is why manufacturers of biotech drugs are mainly from developed countries like America and Europe. 

At least 15,000 thorough documentation is required to discover any new chemical drug. A biologic drug, on the other hand, typically requires 60,000 documents.

A handful of pharma companies in Bangladesh are trying to acquire the skills to make biotech drugs (biosimilars). They have not yet achieved huge success. 

The biotech products of the domestic companies available in Bangladesh are mainly formulation based, the raw materials are imported from abroad. 

Obtaining approval for marketing authorisation of those biotech drugs in Europe and USA are currently not possible. 

Some biotech drugs in neighbouring India have been approved by the FDA and the European Medicines Agency (EMA), that is why those companies can sell their biotech drugs (biosimilars) in America and Europe. 

The demands for Indian drugs are increasing day by day as the drugs produced in India are generally cheaper but have similar qualities to those produced in the western world. 

Soon, India's biotech drugs are likely to find success in the western countries, potentially earning billions of dollars. 

Bangladesh can also take advantage of this if a research-friendly environment is ensured, which has been the key to India's success.

Why is the quality of vaccines so important?

It takes a tremendous amount of scientific skill, resources, infrastructure and time to develop an innovative vaccine, like any other biologics. Unfortunately, most of the candidate vaccines fail to meet the regulatory approval and thus cannot be marketed. 

The successful ones usually take about 10 years before the final product enters the market. Among many reasons, the need for a thorough examination to prove its acceptable safety in humans is a key reason why such a long time is required for the development of a vaccine. 

Vaccine activates our body's immune system to fight against the invading pathogens like viruses. 

However, a vaccine may activate the immune responses wrongly which can have very severe consequences, sometimes leading to the death of healthy humans. 

Incidentally, the development of safe vaccines against some viruses (such as dengue, SARS coronavirus-1, respiratory syncytial virus, RSV) has not been as successful since 1960. 

Candidate vaccines activated the immune systems wrongly and are responsible for immune backfire. 

The world-renowned Sanofi Pharmaceuticals released the dengue vaccine (Dengvaxia) after many years of effort. After receiving dengue vaccine shots in 2016, several people died in the Philippines due to antibody-dependent enhancement (ADE) immune backfire. The criminal charge against Sanofi is still ongoing. 

The so-called Th1 mediated immunopathology can cause the immune system to work against our body, leading to multi-organ failure and death of subjects who received the vaccine. For that exact reason, the development of a new RSV candidate vaccine was stopped for almost two decades. The candidate vaccine against feline coronavirus (feline infectious peritonitis virus) also failed due to a potential immune backfire.

We want to stress that many of the vaccine candidates that were responsible for immune backfire and other severe adverse effects were developed to protect against viruses that cause lung infection (lower-respiratory tract infections), as Covid-19 does. So, it is needless to say that unparalleled caution needs to be exercised to make the coronavirus vaccine safe for humans.
 
Adults suffering from Covid-19 also developed an immune backfire called a cytokine storm. The coronavirus patients die due to excessive immune activation. The million-dollar question which is still unanswered in the scientific community is whether the candidate vaccine would cause immune backfire (Antibody-dependent Enhancement and Th1 mediated immunopathology) or not. 

That is why the think-tank of researchers and clinicians in the field of vaccines are advising not to rush into releasing a vaccine without proper safety analyses and many scientific manuscripts have been published in top-ranked journals like Nature, Science, PNAS, etc. 

Notable vaccine companies which have a lot of experience in working with vaccines/biologics seem to be moving away from the timelines announced initially. The famous American scientist Dr Fauci has been making the American people aware of this issue.
 
Chemistry, Manufacturing and Control (CMC), preclinical, and clinical characterisation of vaccines are crucial to ensure the safety and efficacy of a vaccine. During the preclinical stage, the side effects of the vaccine are tested in animal models. 

Later, the main goal of the first phase (Phase I) of the clinical trial in the human is to thoroughly evaluate whether these candidate vaccines show acceptable safety profiles. Many types of biological assay development and validation under strictly regulated (Good Clinical Practices) conditions are needed to evaluate the safety of a new vaccine. 

Since Covid-19 is a new virus, a substantial amount of time is necessary to validate all those bioanalyses.  Importantly, state-of-the-art facilities and infrastructures needed to evaluate the quality, safety and efficacy of vaccines are yet to be developed in Bangladesh.

The Regulatory Authority carefully evaluates the dossier of several thousand pages before approving the vaccine. This may take a long time. For example, the European Medicines Agency requires an average of 210 days for evaluation of a dossier. 

A considerable number of experts from many disciplines including renowned scientists and clinical researchers evaluate the CMC, preclinical and clinical development. We hope to write in detail about the different stages of vaccine development (CMC, preclinical and clinical development, dossier development) soon.

Ensuring the health and safety of the people is the crucial responsibility of the government of any country. The Regulatory Authority of Bangladesh must make sure that a vaccine is of high quality, safe and effective to safeguard the people in our country before giving commercial approval.  

Rezaul Karim, PhD, is Project Manager of WHO-Utrecht Center of Excellence for Affordable Biotherapeutics, Netherlands. 

Mohammad Sorowar Hossain, PhD, is Executive Director, Biomedical Research Foundation, Bangladesh.