Chasing Polio Eradication: Vaccine Development

Polio Virus and its strategic tool

Poliomyelitis is a life-threatening disease which can cause disability. It is caused by virus called “poliovirus”. This virus spreads from one infected person to another person infecting a person’s spinal cord. An infected person becomes paralyzed and cannot move parts of their body. An infected person may or may not show visible symptoms. Some of the other symptoms includes: Sore throat, Fever, Tiredness, Nausea, Headache, and Stomach pain which can last for about a week and go away on their own. Serious cases of infected people develop more serious symptoms that affect their nervous system and spinal cord causing the following: Paresthesia- Infected person feels like they have pins/needles in the legs. Meningitis- Infection of spinal cord/brain occurring in 1 out of 25 people affected with poliovirus. Paralysis- Infected person loses reflex senses and cannot move their body parts. It is the deadliest one as person becomes disable permanently and dies eventually. The virus affects the muscles that help in respiration and deteriorates it. Children who show the disappearance of the symptoms also develop new muscle pain/weakness as they grow up in 15 or 40 years later. This stage is called Post-polio syndrome.

Poliovirus can be transmitted into the body through the mouth and can be spread through a person coming in contact with the feces of an infected person or if a person inhales droplet from the sneeze or cough of an infected person. Virus resides in the throat and intestine of an infected person and proves to be very contagious. People get infected with poliovirus if they do not clean their hands after using the restroom or touch objects like toys that are contaminated by feces. This was usually observed in developing countries where hygiene was the major point of concern. The transmitted virus can remain in the feces of an infected person for weeks and can affect another healthy person if they come in contact.

In the early stages of vaccine development, two different types of vaccines were introduced against Poliovirus which were: Inactivated poliovirus vaccine (IPV) has been used in the United States since 2000, and the oral poliovirus vaccine (OPV) which is used throughout the world. IPV was developed by Jonas Salk and licensed in 1955. It was a mixture of killed virus which had the ability to induce an antibody-medicated response that stopped the virus from spreading to the nervous system however it did not prevent an immune person from carrying and spreading the poliovirus to others through the fecal-oral route. Moreover, the vaccine was way too expensive than OPV and needed two doses least. Whereas OPV developed by Albert Sabin and approved in 1960 contained live, attenuated wild poliovirus. These were further classified into trivalent oral poliovirus (tOPV) which had weakened live virus for all three strains 1,2 and 3. Monovalent OPVs had the ability to induce an immune response to one strain of virus but had a higher rate of seroconversion than tOPV. OPV doses were administered by untrained volunteers easily but were very potent and sensitive. An infected person was considered fully recovered from polio after receiving three doses of OPV but there was a risk that the virus would relapse to its virulent type strain and can cause paralysis. In April 2016, 155 countries replaced tOPV by the Bivalent Oral poliovirus vaccine (bPOV). Polio type 2 got eradicated in 1955 by usage of tOPV but types 1 and 3 began to show increased cases again in 2007 in India, Nigeria, Afghanistan, and Pakistan.

During these tough times, it was observed that mOPV vaccines reduced type 1 cases but there was an increase in the number of type 3 cases. This relapse and co-circulation of type 1 and type 3 cases of polio virus often required supplementary changes in the immunization activities which involved interchangeability of tOPV, mOPV1, and mOPV2. People injected with tOPV showed a lower immune response when compared to people injected with mOPV. In order to tackle this issue, Dr Walter Orenstein, former director of United Stated Immunization program and WHO Strategic Advisory Group of Experts (SAGE) came up with the idea of a Bivalent vaccine (bOPV) which will contain type 1 and 3 serotypes. There was no safety and efficacy data for bOPV due to which regulatory authorities were speculating whether the vaccine is safe to use for type 1 polio type in place of mOPV.

Advisory Committee for Polio, an independent technical oversight body of GPEI in Nov 2007, recommended that bOPV will be 80% efficacious as mOPV1 and mOPV3 when it comes to seroconversion. They also recommended to conduct accelerated clinical trial considering the urgency. De novo was not necessary to be submitted as bOPV was formulated from the same formulation as tOPV due to which clinical trial directly was passed to phase III. Cochi and Sutter estimated USD 11.5 million to USD 52.9 million for the clinical trial. WHO Research and Product development team helped in trials.

The trials were conducted in India after taking approval to use drug licensure only for data collected in India by the Drug Controller General of India and the Indian National Regulatory Authority. Panacea Biotech based in India who had compliance with Good Clinical Practice guidelines and national laws was selected by WHO to be responsible for supply and monitoring activities of the trials. Blood and stool samples were analyzed at Enterovirus Research Centre in Mumbai which was a part of Global Polio Lab network. WHO started visiting around 10 hospitals to select study sites and informed India’s National Ministry of Health and local state health ministries about the trial. Clinical trial was completed in 5 months by Dec 2008 which had 178 infants enrolled in it. Dr, Harish Verma saw the reports, reviewed them and stated that bOPV was better at protecting children against types 1 and 3 than tOPV and it provides similar protection as offered by mOPV. After this, the production of vaccines increased tremendously and the WHO vaccine prequalification team, WHO Essential Medicines and Health Products department, and their National Regulatory authorities in collaboration with Panacea and UNICEF, and GPEI helped in getting product into the market. National Licensure for bOPV was offered to five manufacturers: Panacea, Haffkine, Bharat Serums and Vacines, Sanofi Pasteur and GSK. A recent survey stated that type 2 poliovirus had been eradicated in 2015, and type 3 had not been detected since 2012.

bOPV vaccine pathway: Research to Marketing

In 1988, the WHO governing body, the World Health Assembly, resolved to eliminate polio worldwide by 2000. However, the smallest possibility/risk of prevalence of wild poliovirus and vaccine-associated paralysis in or close contact with vaccine recipients through the doses of tOPV was a loophole in the complete eradication of poliomyelitis. Hence, a rise in the plateau of wild polio I and III by 2007 in major areas of 4 countries: Afghanistan, Nigeria, Pakistan, and India, gave an urge to develop bivalent OPV vaccine as a supplementary immunization schedule for the eradication of Polio in contrast to tOPV as a routine immunization schedule. WHO experts address the way to eradicate both serotypes at a time through bOPV. However, the challenge lies in proving the safe and effective standards of the bOPV vaccine without data as the national regulatory authorities (NRA’s) —the bodies evaluating the product quality, safety, and efficacy requirements- were reluctant to introduce bOPV without proper results.

The Global Polio Eradication Initiative (GPEI) advisory committee advised conducting a clinical trial to quality bOPV for at least 80 percent as effective as mOPV1 and mOPV3 for seroconversion. In the given crisis, WHO decided to maximize the time and money required to expedite, or fast-track, the normal pathway of research and development through a plan to test the formulation directly into phase III, as the formulation of bOPV was same as tOPV, by removing the component mOPV2. Hence, the need to provide de novo proof of vaccine safety, no longer remain the necessity.

Before its 1990s collapse, India was the most affected developing country with polio and has also been the pioneer-leader in polio science-epidemiology, vaccine prevention- and in both OPV and IPV development. Moreover, the ongoing flow of both Type I and Type III wild poliovirus in India, existing facilities, infrastructure, and placed regulatory bodies made India an ideal location for the clinical trials of bOPV phase III trial. Additionally, the higher cost of conducting the phase III trials, the requirement for approval of the vaccine, for the data collected only in India, and the easy addition of bOPV arm along with tOPV and mOPV evaluation attracted India as a location for trial.

Soon after the evaluation of bOPV as the tool to eradicate polio through clinical results, the committee of WHO expeditated the manufacturing and campaign. Vaccine manufacturers were shared with the campaign schedule, outlining when and on what scale bOPV will be carried out, with projections for a two-year vaccine supply. A regulatory paper was prepared on bOPV, explaining the non-requirement of comprehensive clinical trials and the appropriateness of the Indian non-inferiority trial to authorize the licensure of drugs for various UN agencies. The WHO Department of Essential Medicines and Health Products worked closely with countries and their National Regulatory Authorities (NRAs) to encourage accessible, reliable, safe, and efficient access to medicines, diagnostics, and products.

Vaccine Pricing

The pricing of vaccines is a dynamic, multidimensional matter. Various purchasing factors may affect the price of vaccines, such as procurement process and size, procurement methodology, and contract terms. Generally speaking, vaccine manufacturers follow their own strategies to charge higher vaccine prices in wealthier countries while holding rates lower for countries that are unable to afford the prices on the open market and supported by donors. Advanced market commitments (AMCs) tool strategy where donors provide assistance of funding to vaccine manufacturers and, in return, firms sign a legal agreement to distribute the vaccines to low- and middle-income countries at an affordable price, plays an important role in COVID-19 response.

Vaccines obtained through the program should be free for priority segments of the population at the point of nationwide care, with national allocations assessed by a fair and rational process. For example, the initial doses should go first to health workers and uncontrolled epidemic countries, then to old age and vulnerable populations, and finally to the entire population.

The need for concerted global action

Vaccines can be effective weapons to prevent future outbreaks of emerging infectious diseases from transforming into humanitarian crises. The availability of COVID-19 vaccines is therefore not just a scientific challenge. Past health crises, such as the polio epidemic in the 1990s, the 2009 swine flu pandemic, and the 2014 West African Ebola epidemic demonstrated that organizing globally coordinated action can still be challenging.

Developing and producing a COVID-19 vaccine in 12-18 months on a global scale requires immediate concerted action from governments, foundations, academics, industry, and multilateral and global health collaborations. All involved stakeholders should do everything possible to reduce the timelines for vaccine development and to contribute collectively to ending the pandemic.

There are especially five main areas where collective action is needed.

1. Funding for vaccine production and delivery needs to be mobilized rapidly.
2. The construction of large-scale manufacturing capacity for COVID-19 vaccines.
3. Fair access of vaccines to the world.
4. Well-funded purchasing agents to make a global access program work.
5. Investments for the development and manufacture of vaccines should go hand in hand with the construction of national vaccine delivery systems.

References:

1. What is Polio? (2019, October 24). Retrieved June 23, 2020, from https://www.cdc.gov/polio/what-is-polio/index.htm
2. Rosenberg J, Weintraub R. Chasing Polio Eradication: Vaccine Development. Harvard Business Publishing. 2019.
3. John, T., & Vashishtha, V. (2013, May). Eradicating poliomyelitis: India's journey from hyperendemic to polio-free status. Retrieved June 22, 2020, fromn https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3734678/
4. World Health Organization, Europe. (n.d.). Review of vaccine price data.
5. Schäferhoff, M., Yamey, G., & McDade, K. (2020, April 27). Funding the development and manufacturing of COVID-19 vaccines: The need for global collective action. Retrieved June 23, 2020, from https://www.brookings.edu/blog/future-development/2020/04/24/funding-the-development-and-manufacturing-of-covid-19-vaccines-the-need-for-global-collective-action/