The legend behind vaccines

Authors:
Javier Casellas, M.D., Ph.D.
Enrique Chacon-Cruz, M.D., MSc
Felicitas Colombo, MPA

In the world of vaccinology, Prof. Stanley Alan Plotkin needs no introduction. 

In the 1960s, Prof. Plotkin played a pivotal role in the development of the vaccine against the rubella virus and rotaviruses while working at the Wistar Institute in Philadelphia, where he was a prominent member of its research faculty from 1957 to 1991. Today, in addition to his emeritus appointment at Wistar, he holds the position of emeritus professor of Pediatrics at the University of Pennsylvania.

Another of his most notable legacies is his textbook Vaccines, first published in 1988, for which he has garnered numerous accolades. This award-winning reference guide is widely regarded as the definitive textbook in vaccinology and an essential resource that thoroughly covers every aspect of vaccination and continues to offer reliable information on both existing vaccines and those currently in development.  

One of the ‘founding fathers’ of the Pediatric Infectious Diseases Society, he is also a former member of the Board of Trustees of the National Foundation for Infectious Diseases and former president of the World Society for Pediatric Infectious Diseases. 

Prof. Plotkin has been actively involved in developing some of the most potent vaccines against preventable infectious diseases and is considered one of the world’s leading authorities in that area.

The wisdom that exudes Prof. Plotkin’s every word is difficult to replicate.

Rubella vaccine

Often referred to as the ‘godfather of vaccines,’ Prof. Plotkin is a foundational figure in the development of the rubella vaccine. As a leading advocate, he is optimistic about the prospects of achieving global elimination of congenital rubella.

“Yes. So, I think actually it will be much easier to eradicate rubella than measles. And that is simply because the infectious ability of the rubella virus is much less than that of measles, the so-called reproductive number. And that’s why it has been relatively easy to eradicate rubella from the Western Hemisphere and pretty much from Europe. So, all that we need to do is to extend rubella vaccination to the rest of the world,” confidently articulated Prof. Plotkin.

Widespread vaccination against rubella is already being successfully implemented in countries such as India and China, and it could be extended to other Asian countries, especially when combined with the measles vaccine. Measles-rubella vaccine combinations are easily available, and the Serum Institute of India is making huge quantities of such vaccines. In Africa, however, eradicating rubella presents a significant challenge due to the limited use of the vaccine in many countries. To address this issue, it is crucial for organizations like the World Health Organization (WHO) and local African organizations to actively promote and support the use of the rubella vaccine.

“But in general, I am optimistic that if that is done, there’s no reason why rubella could not be eradicated,” expressed Prof. Plotkin, who shared that his top three success stories in vaccinology are smallpox, measles and Haemophilus influenzae type b.

The rubella vaccine was not fully licensed until 1969. It was later combined with the measles and mumps vaccines to create what is now known as the “triple viral” or Measles-Mumps-Rubella (MMR) vaccine. Today, the widespread use of the MMR vaccine has led to the elimination of rubella in the United States since 2012, with any cases now being imported from travelers coming from other countries.

The mumps virus evolution

The mumps vaccine is based on the attenuation of serial passages from a clinical isolate of the mumps virus known as the “Jeryl Lynn” strain. Additionally, other attenuated strains, such as the Zagreb strain, have also been utilized in the development of live attenuated mumps vaccines.

Since the development of the Jeryl-Lynn strain, a live attenuated virus vaccine administered subcutaneously, the mumps virus has evolved particularly affecting the SH gene. As a result, the original Group A vaccine is now less effective than it was in the past, with current strains predominantly being Group G.

Another challenge with the mumps vaccine is the duration of its efficacy, which may or may not be improved by switching from A strains to G strains. Despite these challenges, Prof. Plotkin remains confident that adapting the vaccine to address these changes could lead to a formulation with longer-lasting efficacy.

“I’m relatively optimistic that that change would give longer efficacy, but that remains to be seen. So, what we can do certainly is reduce mumps, the occurrence of mumps in children. Whether we can also prevent mumps in older people like college students remains to be seen,” concluded Prof. Plotkin.

Avian flu mutations and pandemic threats

The remarkable ability of influenza viruses to mutate and cross species leaves humans at risk for future pandemics. Experts monitor influenza viruses in various species, including birds, to assess the potential for these viruses to cause a pandemic. Prof. Plotkin prefers to focus on preparedness rather than speculating on potential scenarios.

“Well, this is, of course, a controversial question these days. And some people are pessimists and believe that the avian flu will spread to humans and cause a pandemic. And some are relatively optimistic and think that an H5 containing strain will not spread to humans. And, you know, I think the honest answer is we don’t know. And that we must take precautions. Now, I am not, I would say, very pessimistic,” he shares.

Viruses outside of H1, H2, and H3 subtypes have not yet spread to humans, possibly due to underlying biological reasons. To prepare for a potential emergency, Prof. Plotkin proposes establishing a substantial initial stockpile of vaccines. Once this supply is in place, production could be rapidly scaled up if needed.

“I don’t feel that we should create billions of doses yet. But I think it’s reasonable for us to take some precautions and let’s say create a million doses that would be available in the case of an emergency. And of course, the other part is for us to maintain, let’s say, surveillance of influenza and make sure that H5 is not spreading widely to humans,” he proposes.

Prof. Plotkin notes that while surveillance efforts are reasonably organized in most of the Western Hemisphere, many regions of the world lack such infrastructure. Expanding surveillance campaigns in these underserved areas would be highly beneficial.

“That being said, so far, the mutations that have occurred in influenza have been detected relatively quickly in parts of the world where there is surveillance. So, the situation is not terrible, but it could be improved,” he claims.

Prof. Plotkin feels that, so far, the cases have not reached a level of severity to push the panic button yet. Hence, producing enough vaccine doses for the entire world at this stage would be costly and potentially useless. However, he emphasizes the importance of preparedness, noting that “our predictive ability is not great.”

Inequity is in the eye of the beholder

Since the COVID-19 pandemic, the public health system has faced increased scrutiny over how inequities in vaccine manufacturing, implementation, and distribution impact outcomes in both developing and developed countries. With a long-term viewpoint, Prof. Plotkin reminds us of the progress made in vaccine manufacturing capabilities and the lessons learned from past challenges.

“My thoughts are, actually, somewhat optimistic in that there has been, fortunately, a tremendous change in my lifetime with regard to manufacturing ability. It’s not optimal, but it’s certainly better than it was,” commented Prof. Plotkin, who has had a role in the expansion of Serum Institute of India, a biotechnology and biopharmaceuticals company, to become one of the world’s largest vaccine manufacturers. 

In addition to India, other examples of countries that have started producing vaccines locally are Brazil, China and Thailand. While some regions of the world remain under-vaccinated, Prof. Plotkin asserts that the drawback is not related to vaccine supplies but rather to economics, political will, and the capacity to implement vaccination programs effectively.

“It’s the economics of vaccine purchase and the desire to have vaccines and, also of course, the ability to use them. So, what I would say is that potentially vaccine production is less of a problem now than it is the desire to use vaccines,” claims Prof. Plotkin, who fervently believes vaccination should be mandatory.

Lessons from the COVID-19 pandemic: surveillance 

Public health surveillance is crucial for informing decision-making in public health. The onset of the COVID-19 pandemic in early 2020 prompted a significant acceleration in the development of technologies designed to enhance monitoring efforts. As a result, the pandemic has led to notable changes and advancements in public health surveillance methods.

“The first thought is about surveillance that in the case of COVID, as you know, what happened was a virus of bats managed to infect humans in ways that are still controversial,” confirms Prof. Plotkin.

Be that as it may, the virus did manage to jump species, highlighting the fact that viruses affecting humans have historically originated from animals. Prof. Plotkin emphasizes that a key lesson from this experience is the need to be prepared for a range of viruses that might potentially jump to humans.

“And that’s something that should yield interesting information. But of course, we also need surveillance. That is, isolating viruses from people, especially those in contact with animals, animal workers, dairy workers, etc., to see what viruses they’re picking up,” sustains Prof. Plotkin, who claims there is research showing that people are acquiring viruses that give them antibodies in areas such as China and other countries in Asia. 

As a result, many organizations, including CEPI (the Coalition for Epidemic Preparedness Innovations), which Prof. Plotkin helped to establish, are actively monitoring various families of viruses present in animals to assess their behavior and potential risk to human health.

“So, I think we learned the lesson and I’m optimistic that we won’t make the same mistake again by not surveying animal-to-human transfer,” he concludes. “And I think that’s the only way we’re going to be prepared for new viruses that jump to the human species.” 

Vaccines within 100 days

It is undeniable that messenger RNA technology has enabled scientists to go from a new sequence to a messenger RNA vaccine in 100 days. 

“But I would add to that, that I am one who counsels that we should not depend on messenger RNA technology only. It’s great for quick response, but it is not always the best way of vaccinating. As you know, there are basically two difficulties,” he continues to explain that one is the duration of the response and the other is the capacity to produce good T cell responses. 

Prof. Plotkin shares that, depending on the immunological characteristics of the disease, several established technologies can be used. If a long-lasting response or a strong T cell response is required, there are alternatives to RNA vaccines.

“So, my argument is, yes, we should be able to respond quickly with an mRNA vaccine, but our work doesn’t stop there. We should go on to see whether other types of vaccine would give the immune responses that we need permanently. So, I think that’s a practical scheme,” he debates.

Prof. Plotkin believes that using different lipid nanoparticles, more effective adjuvants, or employing self-amplifying mRNA technologies might not only achieve a rapid response similar to that of conventional mRNA vaccines but also provide a longer duration of immunity.

“I think it’s very likely. Obviously, [vaccine development] it’s going to depend on the agent, and that is, for example, whether it’s primarily a mucosal infection or whether it’s systemic, and that has obvious impact on the type of technology that you want to use. So, it’s difficult to give a general answer. I think [the choice of vaccine technology] it’s going to depend on the specific agent, but it’s important that we don’t put all our eggs in the mRNA basket,” he deliberates.

Correlates of protection for vaccine development

Correlates of protection allow scientists to predict vaccine efficacy, which is crucial, especially when evaluating multiple candidate vaccines. In many instances, a specific immune response can be identified as a reliable correlate of protection. However, confusion can arise when several types of immune responses need to be considered, as each may play a role in the overall protection provided by the vaccine.

“And, of course, that’s true. But what a [an established] correlate of protection serves is it has predictive value. It’s not to say that other biological responses are [not] valuable, but it tells you what you can use to predict that a vaccine is going to work,” shares Prof. Plotkin, who has authored more than 800 publications, most concerning the safe and effective use of vaccines.

Understanding the correlate of protection is important because it allows scientists to focus on enhancing this specific immune response in various ways. Although a single immune response alone may not be sufficient for comprehensive protection, identifying a correlate enables predictions about vaccine efficacy. This is valuable when comparing different vaccines or assessing responses in a population, helping to determine the overall effectiveness and value of a vaccine.

“Now, having said that, it’s important to recognize that biology is complex,” Prof. Plotkin points out.

In the case of COVID-19, the situation is more complex because it primarily affects mucosal surfaces, making it challenging to determine a single correlate of protection. This complexity arises from the fact that multiple correlates of protection may be relevant, complicating the process of identifying and measuring the most effective immune responses.

 “That is, there are correlates against infection, and there are correlates against disease. In general terms, antibodies will prevent infection if the antibody titer is high enough. But, if infection occurs, T cell responses are key to preventing systemic symptoms. So, you know, life is complicated,” explains Prof. Plotkin, who further notes that, in the case of measles, protection can typically be predicted based on antibody titer levels alone.

He believes that science has made significant progress in determining correlates of protection for COVID-19. However, a key gap remains in identifying correlates of protection specifically against other mucosal infections. Additionally, for many other diseases, clear correlates of protection are still not well-defined. The more complex the biology of a disease, the more challenging it is to pinpoint a reliable correlate of protection.

“Cytomegalovirus is a good example of the complexity of correlates. And there’s no single correlate that is good [sufficient]. And so, we need a lot of work there. But there are other examples, notably HIV, where we’re far from identifying a correlate of protection. And mucosal infections in general, I mean, rhinovirus, various other things. I think we need a lot of work to develop correlates of protection,” he ponders.

Foytomegalovirus (CMV) is related to the viruses that cause chickenpox, herpes simplex and mononucleosis. CMV may cycle through periods when it lies dormant and then reactivates. Rhinoviruses are the most frequent cause of the common cold and are a common viral trigger for asthma attacks.

“On the other hand, I mentioned chikungunya before. And, you know, before there was a vaccine, we knew very well what the correlate of protection is. And, as soon as we reproduced it, that is, serum antibody, that was it,” recalls Prof. Plotkin.

For group B streptococcal disease, “I think it’s pretty clear that [serum] antibody to that organism is going to protect against serious disease. But what is not clear to me is how you can prevent colonization. And so, I think more work needs to be done on that issue.” he concludes.

Prof. Plotkin emphasizes the importance of improving the process of evaluating vaccine efficacy without expecting a predictive value of 100%. Instead, the focus should be on determining whether the vaccine will be effective to a significant degree when widely used.

Prof. Plotkin’s lifelong work on vaccines spans over six decades and has resulted in significant reductions in both morbidity and mortality globally. An optimist at heart, his steadfast commitment to guiding his research with rigorous science has earned him profound admiration and respect from his peers around the world.

Prof. Stanley Plotkin’s bio