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Evolution of vaccinology and vaccines for Covid-19: Where do we stand now?

  • Published at 04:02 pm July 27th, 2020
Evolution of vaccinology and vaccines for Covid-19: Where do we stand now?
Photo: Professor Gottfried Kremsner injects a vaccination against the coronavirus disease (Covid-19) from German biotechnology company CureVac to a volunteer at the start of a clinical test series at his tropical institute of the university clinic in Tuebingen, Germany, June 22, 2020. REUTERS/Kai Pfaffenbach/File Photo

Because of the unprecedented public-private co-operation, some vaccines for Covid-19 may reach the commercial stage within 12 to 18 months instead of the usual 10–15 years required for normal vaccines 

The purpose of vaccination is to train the immune system to fight against specific germs. It essentially means arming the body with a tool to fight against future infection. In many cases, this tool is the germ itself. 

Edwards Jenner’s use of cowpox pus to protect a thirteen year-old boy from the infection of smallpox in 1796 was a ground-breaking invention at a time when the concept that disease could be caused by germs was not even well-established. About one hundred years later, the invention of vaccines for anthrax (1881) and rabies (1885) by Louis Pasteur, revolutionized the use of germs for preventing diseases. Ever since, vaccines have been one of the primary tools to fight against a number of diseases.  

Invention of vaccines is considered one of the most important public health achievements for mankind. With the help of vaccines some diseases have been eliminated once for all (such as smallpox) and many have been brought under control (such as polio). During this difficult time of the Covid-19 global pandemic, our best hope is that the invention of an effective vaccine against this invisible enemy will save the humanity. 

The process of vaccine development has come a long way with so many success stories. In the past one hundred years, the arts and science of vaccine development have evolved – from the use of live-attenuated or weakened germs to genetically engineered germs, and most recently breakthroughs in the DNA and RNA vaccines. 

Vaccines types and how they are produced

Based on the nature of the active ingredients, vaccines can be classified into different types. Live-attenuated vaccines are weakened versions of the germs that cause the disease. They are alive but weakened to such a degree that they cannot cause disease any more. Such vaccines can offer long-term immunity against germs. Vaccines used against measles, mumps, rubella (MMR), smallpox, chickenpox are made out of live-attenuated germs. 

Inactivated vaccines are dead versions of the disease causing germs – killed by heat, chemical or radiation treatment. Such vaccines can not provide life-long immunity, usually requiring several times immunization (boosting shots) in order to get ongoing immunity against the diseases. Vaccines for hepatitis A, polio, rabies are inactivated vaccines made out of their respective germs. 

Subunit, recombinant, polysaccharide and conjugate vaccines, etc are made out of a small part of the germs’ chemical constituents. These classes of vaccines are varied based on the target – they can be protein, sugar or modified products of the antibody produced in the human body in response to the infection. They usually give a strong immune response and target the key parts of the germ responsible for infection. 

Vaccines for hepatitis B, human papillomavirus (HPV), whooping cough, meningococcal diseases belong to these classes. 

Toxoid vaccines are toxins produced by germ that causes diseases. They create antibody specific to the toxin that causes a disease instead of the germ itself. Vaccines for diphtheria and tetanus belong to this class.

Emerging technologies for vaccines 

Recombinant DNA technology plays a vital role in vaccine research, development and manufacturing. Using this technology, a specific gene of the germ can be combined with other organisms allowing production of the gene’s product. 

Using such technology, various vaccines can be made by bacteria or yeast cell-cultures and in plants. A small piece of DNA of the disease causing germ is inserted into other cells to instruct them to produce the active ingredient for vaccines, usually single protein or sugar. Hepatitis B vaccine is produced by inserting its DNA piece into the yeast cells. 

In this century, both the DNA and the RNA vaccines will likely play dominant roles. Using bioinformatic tools, vaccines can be designed.  DNA and RNA vaccines can be produced by chemical synthesis and/or by enzymatic means. They are designed to send coded messages to cells to produce antigen so that a specific antibody against a specific germ is produced. 

In the past, the main challenge was to obtain the effective delivery systems so that they could penetrate into the cell. By using new delivery systems such as lipid nanoparticles, chemical modification of the synthetic DNA or RNA molecules, etc, the DNA and the RNA vaccines will be able to provide new efficiency in delivery. And these are likely to arrive at the production stage and reach medical practitioners very soon. 

So far, no DNA or RNA vaccines have been approved for human uses, but using similar technologies a number of genetic diseases are being treated now. Among the leading Covid-19 vaccine candidates, some are based on DNA or RNA vaccines.

Regulatory approval process for drugs and vaccines: Covid-19 will likely be an aberration 

Vaccines are given to healthy people to prevent illness. Therefore, the testing and safety standards are set much higher than what’s accepted for other drugs. This translates into years of clinical trials. Researchers must test multiple candidates over years, or sometimes decades following sequential steps. 

In the traditional route, each vaccine development undergoes 5 separate steps. The first is discovery research, which can take 2-5 years and involves lab-based research looking to find ways to induce an immune response at molecular and cellular level. 

After that, the pre-clinical stage, which can take 2 or more years and involves testing on animal models to assess the safety and suitability of potential vaccine candidates for human use. Only selected candidates move to the clinical phase. At discovery and pre-clinical stages, many candidates are screened, and majority candidates fail simply for not meeting expected criteria for pursuing subsequent steps.  

Next, clinical development involves testing potential vaccines in human subjects and has three phases: Phase I determines safety, doses and immune response and it can take up to 2 years and requires 10-50 healthy volunteers to take part in trials. Phase II determines efficacy and side effects, can take 2-3 years and requires hundreds of volunteers to take part in trials. Phase III monitors efficacy and adverse side reactions and can take 5-10 years, requiring thousands of volunteers to take part in trials. Only about 10% of the vaccine candidates entering into human clinical trials may reach to commercialization phase for using as drugs or vaccines 

After clinical development finishes the 3 phases, there is regulatory review and approval, which involves submitting data and information to regulators to gain approval for vaccines and can take 2 years. 

Finally the manufacturing and delivery requires specialist facilities that are highly regulated and expensive to develop.

Under normal circumstances, following this traditional route, a vaccine development could take more than 10 years and cost can run into billions of dollars. The success rate is very low, because every drug and vaccine must meet safety, efficacy and effectiveness requirements. 

During this global pandemic, some of the leading vaccine candidates are placed in fast track which allow quicker review and approval. For example, Operation Warp Speed (OWS) of the US government is designed to help industry for speedy development, manufacture and distribution of new vaccines for Covid-19. 

Because of this kind of unprecedented public-private co-operation, some vaccines may reach the commercial stage within 12 to 18 months instead of 10–15 years required for normal vaccines.  

The ongoing Covid-19 vaccine development

The pandemic has created huge public-private partnerships where researchers worldwide are working around the clock to find a vaccine. As of mid-June, about 200 vaccine candidates are in various stages of development around the world. Some of them have leaped into Phase III clinical trials. 

Vaccine candidate mRNA-1273 by the US based biopharmaceutical company Moderna is an RNA based vaccine candidate. mRNA is a messenger molecule that serves as an intermediary molecule in the decoding process from the DNA to protein. 

This particular mRNA codes the spike protein of the coronavirus, which is essential for entering into the human cell and causing infection by binding to the cell-surface protein ACE2. This mRNA platform provides significant advantages in speedy vaccine design and efficiency in large scale manufacturing. The mRNA-1273 has finished the Phase II trial and Phase III is underway. 

The vaccine candidate BNT162b1/b2 is developed by Pfizer and BioNtech. They are chemically modified mRNA, formulated in lipid nanoparticles. BNT162b1 encodes an optimized Covid-19 receptor-binding domain (RBD) antigen while BNT161b2 encodes an optimized full-length spike protein antigen. It is now in phase I/II clinical trials in the USA and Germany.

Similarly, the mRNA-based vaccine by CureVac AG and the German federal government is also an RNA vaccine, which provides a strong and balanced activation of the immune system. This has passed the Phase II trial and the pre-clinical results have shown virus neutralizing titers and T-cell response to the candidate.   

Vaccine candidate INO-4800 by Inovio Pharmaceuticals, is a DNA vaccine. This is a small piece of circularized double-stranded DNA, called plasmid form, codes specific gene of the virus which eventually leads to the production of specific antibody to neutralize the coronavirus. 

This vaccine candidate does not need special arrangement such as cool temperature for storage and transport. Therefore, it could offer a better alternative for delivery in regions where such infrastructure does not exist such as in poor Asian and African nations. 

Vaccine candidate AZD1222 (in Phase III trial), jointly developed by Oxford University and AstraZeneca is genetically engineered adenovirus. This virus is related to the virus that can cause cold fever. This germ carries the gene coding the spike glycoprotein of the Covid-19 virus. Spike glycoprotein is found on the surface of Covid-19 virus and plays an essential role in the infection pathway. Vaccine candidate Ad5-nCoV– by CanSino Biologics, China, is in Phase II, which is also a recombinant adenovirus.

Countries like Bangladesh will wish for some vaccines over others 

Among vaccine candidates, most are likely to never reach patient care, ie they will not reach the commercial production stage successfully. But a couple of them will certainly reach the doctor’s office for patient care in the next one or two years. 

Unfortunately, it does not mean that developing countries like Bangladesh will be benefited immediately, as large scale manufacturing and distribution will certainly be a major challenge. But some vaccines will be better than others in terms of benefiting developing countries. 

If DNA and RNA vaccines come out as the first winners, they may reach us much quicker than anticipated, because they can be manufactured at a much larger scale and more quickly than other vaccine candidates.

Dr Mazharul Islam Rana is working at the Department of Chemistry of Bath University, UK. He is one of the coordinators of Forum Vision 2041, a forum of Bangladesh-born academics/scientists working at home and abroad. He is also a founding member of the newly established University of Skill Enrichment and Technology (USET), Narayangonj, Dhaka.

Dr Mong Sano Marma is a Principal Scientist at Miltenyi Biotec, Boston, USA. He was one of the lead scientists of the team which successfully sequenced the genome of Hilsha fish. He is an experienced scientist in molecular bio-technologies and inventor, holding a number of US and international patents relevant to new generation DNA sequencing technologies.

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