With pandemic fatigue affecting not only the economy but our mental and physical health, it is not a surprise many are looking forward to vaccines as the saving grace.
At first, I thought writing an article on coronavirus vaccines was a bit premature considering the fact that while the speed of biologicals development has far exceeded our expectation, media and press releases have jumped the gun in the race to vaccine development and in the process may have missed out on some information that is up for discussion before deciding to join a clinical trial, get a vaccine when available and other issues that some of us may not have even thought about.
So let’s look at some facts and questions you probably didn’t consider asking (or were afraid to ask).
- How many vaccines are in development?
The New York Times Vaccine Tracker provides a simple overview of how many and what vaccines are in the various phases of development. It also summarizes what that phase of development entails. For example, phase 1 of drug development looks at safety and dosage. While the objectives of the various phases have specific objectives, the over-arching goal in any drug development process is SAFETY.
The regulatory spectrum ranges from phase I to approval status, with some drugs being approved on a limited basis early on. There can also be a combination of these various phases in order to accelerate the drug development process for emergency use.
As of November 29, 2020, there are six vaccines that are approved in some countries under limited use. All are either manufactured in China or Russia, with China, Russia, and the United Arab Emirates using these vaccines on a limited basis.
2. Are they effective?
All studies will still need to go through a peer review before it is published by a reputable journal. So far, the data on efficacy is limited to media releases by the developers of the vaccine.
But what does effectivity (or efficacy for that matter) mean?
The term efficacy is used in controlled clinical trials. Effectiveness is measured when the general population is using the product already. In short, until the drug/biological is in the market, we will not know its effectiveness. Hence, efficacy is not the same as effectiveness.
A clinical trial is not a real-world setting. Subjects are included based on inclusion and exclusion criteria, which are most likely stringent. For example, children who may not be initial targets for COVID19 vaccines will be the last to be studied. Currently, only China’s Sinovac COVID19 vaccine is doing phase III clinical trials in children.
Effectiveness cannot be measured in controlled trials, because the very act of including non-real world scenarios distort the usual practice of a clinical trial.
In the real world – can patients who have had coronavirus infection receive the vaccine? To rephrase the same question, this time emphasizing on safety issue, can patients who have had coronavirus infection or are positive for SARS-CoV2 safely receive COVID vaccines?
ADE (ADE) or antibody dependent enhancement phenomenon is a real world phenomenon that can pose safety issues on a long-term basis.
3. Safety and ADE
Short term safety concerns have been addressed by many of the manufacturers. Most of them were anywhere from mild to moderate reactions.
Some vaccine trials have come to a pause. It is not uncommon to encounter pauses during clinical trials. When investigators find worrying symptoms, they try to determine if it is related to the drug, place the trial on pause, and investigate the case. Two outcomes result after an investigation – the trial is resumed or abandoned. If the adverse event in the trial paused due to highly concerning safety issues, (remember it is still in a clinical trial phase) that means that safety issues in a few when extrapolated to a larger population can be dangerous.
Which goes back to the concept of ADEs. In ADE, cross-reactive antibodies generated by a previous exposure to a heterologous strain are believed to facilitate the within-host replication of a second invading strain. This phenomenon has been seen in Dengue, HIV, and a variety of flaviviruses and other viruses.
We need to remember that it has been barely a year since the pandemic started. The race to drug and vaccine discovery is even much shorter. Which brings us to the issue on long-term side effects – a possibility – that can only be evaluated years after the vaccine is in the market.
So if one has had SARS-CoV2, was asymptomatic, had never been tested, believes he never had the viral infection, could he safely receive the vaccine? Remember, it is possible that because almost 10 percent of people who are tested have no symptoms at all and yet turn up positive on RT-PCR testing, you may have had the virus but did not know you had it. If this is a real world scenario, then it is likely too that ADE may be a potential issue with vaccine safety.
Clinical trials have not yet begun in children and pregnant women and other immunocompromised groups. Whatever recommendations there will be when the vaccines are launched will be for healthy human subjects who were negative to the coronavirus from the get go.
4. Herd Immunity
Best laid plans for immunization programs is aimed at achieving herd immunity.
Otherwise called “community immunity”, herd immunity is achieved when enough people are immune when transmission of the disease is reduced or eliminated. Herd immunity is achieved by protecting people from a virus, NOT by exposing them to it.
The concept of immune response to COVID19 is still unclear. The percentage of people that need to have antibodies to achieve herd immunity for coronavirus is not yet fully understood as the virus manifests anywhere from asymptomatic to severe disease in those affected. Other questions left unanswered are, among those who do develop antibodies, how long do these antibodies last, and we know now that there are patients who can get reinfected. Is the severity of disease correlated with the amount of antibodies produced and the protection against getting COVID19 in the future? If you’ve had COVID19, does that exempt you from getting the vaccine? Or if and when you get the vaccine this time around, is it safe?
Following the same trend of thought, if you do get immunized, will you need boosters in the future and how frequent should you get it?
Based on mathematical modeling, if the vaccine is found to be at least say, 70 efficacious, you may need to provide immunization to at least 60-75 percent of the population at risk.
No vaccine is 100 percent effective. Sadly, that’s a fact. People respond to vaccines in various degrees. And even with antibody responses, some patients have antibodies that wane quicker than others over a period of time.
Which makes us return to the concept of “effectiveness”.
If a vaccine is touted to be say, 70 percent effective, what does that imply? Effectiveness estimates how much of the disease will drop in vaccinated people on the presumption that the rate of infection among people who do not get vaccinated is 1. In layman’s terms, it means that 70 percent of the people who developed COVID19 without being vaccinated would not have gotten it had they been vaccinated.
With these unknowns, it is still not reassuring that if one gets vaccinated, one will NOT get COVID19 (as in any other vaccines, there is no 100 percent assurance). If one does get COVID19 in spite of getting the vaccine, will it be mild or can the disease progress to severe/critical and can one still die from COVID19 in spite of having received the vaccine?
If one does get an infection even when one is immunized, is that person contagious? (I am definitely sure that the person is and will still have to follow all the quarantine and mitigation measures that we’re currently practicing.)
The 2-3 million doses that the government and private sector are planning to purchase will probably not make a significant dent on how the pandemic is playing out in the Philippines. With a population of 110,000,000 spread over 7,630 islands in this archipelago, even targeting the most highly dense populations will not be enough to curtail community transmission.
The concept of herd immunity teaches us, that in order to make sure that we nip the transmission in the bud, then a large percentage of the population need to get immunized now (and not spread out over a 2-3 years period) – so that if say 70% of those immunized don’t get sick, then the remaining 30% who are not immunized will not get sick by default.
Because there are many candidate vaccines out there, one needs to remember that they come in different “platforms”. These so-called platforms serve as the delivery systems for the body’s immune response to a foreign substance, in this case, SARS-CoV2.
This is being discussed on the light of interchangeability.
In short, if the patient receives a vaccine with a mRNA platform (synthetic messenger RNA), can he receive the second dose with a vaccine with an inactived virus platform?
Vaccines from similar platforms (e.g., mRNA) MAY theoretically be interchangeable. However, adjuvants and other substances added to the vaccine in order to improve the deliverability or immunogenicity may not be the same.
For now, as a general rule, because of lack of interchangeability studies, one cannot and should not even consider purchasing multiple source vaccines for immunization programs. Not only will it impact on the effectiveness of the vaccine but safety issues can be a nightmare to health authorities and regulators when several options are cascaded at the get go.
6. Cold Chain and Storage
Finally, one needs to consider preserving the integrity of the vaccine.
Cold chain refers to temperature-controlled supply chain. The delivery of vaccines to every part of the world, every region, every province, city, town, municipality and barangay is a complex undertaking.
That chain is a series of coordinated linked events related to preservation of the ideal temperature from manufacturing to storage, management and transport until the time of administration to the patient or recipient. Disrupting that chain is disastrous because the integrity of the vaccine becomes compromised. For example, if the vaccine will require -80 degrees C storage capacity, one will need to know how long it can be thawed and what appropriate timing from thawing to administration to patient is best so as not to affect the potency of the vaccine.
The most common problem encountered with vaccines when not stored properly is a decline in the potency. Which virtually leads anywhere from minimal to no protection at all, giving patients a false sense of security, increasing the risk to developing disease, and increasing the risk of disease to others in the community because of failed immunization.
As more information eventually unfolds in the future on COVID19 vaccines, recommendations will change. Answers will be provided.
For now, patience is a virtue. And we have no recourse but to make sure that we contain the pandemic, the old fashioned way.
References (and additional reading materials)