The charm of history and its enigmatic lesson consist in the fact that, from age to age, nothing changes and yet everything is completely different.
—Aldous Huxley
Early this month, the Pfizer/BioNTech mRNA vaccine was approved within 11 months of the discovery of the Covid-19 virus. Pfizer vaccine is the most rapid vaccine deployment in history, completing all the mandatory stages (the Russian and Chinese vaccines have been approved before Phase III trials).
The history of vaccine development has been chequered and not very encouraging. It took 26 years to develop a vaccine for the human papillomavirus (for cervical cancer) and 25 years for a vaccine for rotavirus (against gastroenteritis). Thirty-five million people have died of AIDS in the last 40 years. Since 1987, thirty vaccine candidates have been tested in human clinical trials but no candidate has cleared the phase III trial till date. Malaria affects 400 million people annually, resulting in two million deaths. Over $100 million is spent annually on malaria vaccine research but there is no vaccine in sight. There is no vaccine against other coronaviruses like SARS and MERS.
How (and why) is it that within 100 days of the discovery of Covid-19, there were 45 vaccines in development? How was it possible that in just 63 days, Moderna could develop a vaccine candidate, do animal trials and then inject in the first volunteer. Today we have over 321 vaccine candidates in various stages of development with 40 vaccine candidates in human clinical trials, nine in phase III trials, and two already approved.
There are broadly four steps of vaccine development and deployment which include understanding the structure of the virus, studying the interactions of the virus in the human body to find a suitable vaccine candidate, clinical trials followed by regulatory approval, and large scale production.
Traditionally, upon identification of a novel virus, the virus had to be taken apart piece by piece to understand its different components. A decade ago, this used to take one to two years. There have been tremendous advancements in genome sequencing in the last decade. As an example, the cost of human genome sequencing has dropped from $100 million in 2001 to just $500 in 2020. With the advanced technologies now available, the scientists in Shanghai could decode the virus in less than 40 hours after receiving the samples. Sequencing the genome of the virus is crucial for developing specific diagnostic tests and identifying potential vaccine candidates. The second step is to identify which elements of the virus trigger an immune response in our body, purify that agent (epitopes), and test it on animals. A decade ago, this process would have taken another one to two years, sometimes more than five years. Various technology breakthroughs along with the use of computational models and Artificial Intelligence have helped shrink these steps to weeks if not days. Moderna vaccine candidate was developed within two days of the publishing of the virus structure.
The last decade has seen the development of computational methods to discover new candidate drugs and vaccines in silico (research conducted by computational models or computer simulations). Machine learning-based models have offered inexpensive and rapid methods for the discovery of effective viral therapies. Artificial Intelligence is increasingly being used in predicting the properties of a potential compound such that only compounds with desired properties are chosen for further development, saving time and money. The third and most crucial step is clinical trials. Like all medicines, vaccines go to clinical trials after they are tested in experimental animals. Based on typical FDA processes, the time for clinical trials could be many years, as the regulatory body requires vaccines to undergo at least three phases of clinical trials before the application for approval is submitted.
Phase I is to assess the safety of the vaccine candidate in a few healthy volunteers (between 20 to 80 volunteers). In phase II, the vaccine is given to a larger number to see if the vaccine has the potential for a protective immune response and to study the candidate vaccine’s safety, proposed doses, schedule of immunisations, and method of delivery (such as oral or nasal or injection), etc.
In phase III, several thousand participants are divided into two groups. One group receives the vaccine, and the other receives a placebo (like a distilled water injection). This phase aims to compare the two groups and establish if the vaccine is effective at preventing the disease. Phase III trial is the most time-consuming step because researchers have to wait for enough participants to be exposed to a virus naturally. Pfizer completed the phase III trial when there were 170 cases of the disease in its trial of around 43,000 volunteers, of which 162 were observed in the placebo group and eight in the vaccine group. Historically, from Phase I clinical trials, around 90% of vaccine candidates fail to make it to final approval, and from Phase III, 25% fail. The investment by a manufacturer in a vaccine candidate typically exceeds $1 billion.
It usually takes one to two years for regulatory approval. Regulatory filing is required after each phase. Due to the pandemic, regulators allowed combining phases I and II trials in some cases. Some regulators (like the UK) have gone for a “rolling review” approval process where they have been studying and auditing the data as it comes instead of starting the review after the complete data is received. Though the regulators are working overtime to evaluate the vaccine candidates, there is a need to develop disruptive technologies and protocols for clinical trials. In terms of the structure of clinical trials, the process of randomised control trials has essentially remained the same since the first such trial of streptomycin in 1946 in the UK. How can we reimagine the clinical trial protocols that imbibe new computational technologies? We also need to adopt an “adaptive trial” framework where the trial can be tweaked as the results come in. How can we find a solution to the paradox of having a vaccine candidate within 42 days which eventually gives 95% efficacy but requires a clinical trial extending ten months while millions die?
Pfizer and Moderna have used a novel mRNA technology for their vaccines which are faster to develop. This new technology does not require a weakened or dead virus for the vaccine. The genetic material mRNA is easy to make in a laboratory, and manufacturing an mRNA vaccine rather than a protein can save months. The mRNA technology only needs the genetic sequence of coronavirus to make a vaccine and no live virus has to be cultured and grown in labs. This new technology is like writing a software upgrade instead of finding new hardware each time.
The Oxford vaccine also uses a scaffold or a ‘carrier virus’ made in a lab to inject the active agent which triggers immunity. The same ‘carrier virus’ is used for various vaccines. Thus we have entered the age of designer and editable vaccines.
The fourth step is rapid manufacturing and deployment. The manufacturing of various Covid vaccine candidates is already underway before clinical trials have concluded. A tremendous amount of risk capital has been available for this to happen. In the US, the White House’s “Operation Warp Speed” has brought together public and private stakeholders to deliver 300 million doses of the Covid-19 vaccine by January 2021. The US government has given grants of over $5 billion for vaccine development. Governments across the world have given out advance purchase contracts for more than six billion doses even before a single vaccine was approved. Together, Pfizer, Moderna, and AstraZeneca will be producing over 1.5 billion doses by June 2021. However, some questions still remain. How long does the immunity to the virus last? Immunity to cold-causing coronaviruses typically lasts only one to two years suggesting that people might need seasonal shots of any Covid-19 vaccine.
To summarise, rapid advances in multiple technologies will lead to even faster development of drugs and vaccines in the future. Today, drug and vaccine development has moved from cell culture and fermentation processes to computational models, data analytics, and AI. The huge amount of money pumped into vaccine research this year will lead to the rapid adoption of new technologies. In the future, we may have a vaccine within three to four months of a new outbreak or a pandemic that may impact the developed world. The global pharma companies and scientific institutions may still not have much interest in the pandemics of the developing world including TB, Malaria, AIDS, etc, and these diseases will continue to kill millions despite the technological advances.
The writer is the founder of NeuroEquilibrium, an Angel Investor and Healthcare thought leader.