Sabin’s live attenuated virus vaccine had many advantages over Salk’s vaccine. It was easier and cheaper to manufacture because, unlike Salk’s vaccine, inactivation of the virus by careful treatment with formaldehyde was not required. Sabin’s vaccine was also efficacious at lower doses, thus requiring fewer quantities to be manufactured. Administering Sabin’s vaccine did not require syringes or needles. Vaccination involved swallowing a drop of fluid on a sugar cube. The live attenuated virus first infected the intestine, and elicited both IgG- and IgA-type antibodies. Recall from the immunity chapter that IgG protects the blood and IgA protects surfaces of organs. IgA antibodies induced by Sabin’s vaccine prevented the poliovirus from attaching to and infecting intestinal cells. Salk’s vaccine, in contrast, only induced an IgG response, so it was able to block the spread of the virus only in the blood and nervous system. If someone vaccinated with Salk’s vaccine got infected, the virus could still infect the intestine and potentially spread to others via the feces. For reasons that are not completely understood, Sabin’s vaccine induces lifetime immunity, while Salk’s offered protection only for a few years. For these reasons, Sabin’s vaccine soon became the standard vaccine used around the world.
Mainly because of the large-scale use of Sabin’s vaccine, poliovirus has largely been eradicated from the planet. Only a few natural infections occur now, mainly in Pakistan and Afghanistan where polio is still endemic. Sabin’s vaccine is a live RNA virus. While it does not thrive well in humans, it does replicate in us. Since RNA replication is error prone, the virus in the vaccine could mutate to become dangerous again. The mutated virus could spread to others and cause paralysis. Indeed, most of the cases of polio seen today outside the endemic areas are caused by such mutations of the live virus in Sabin’s vaccine. Because of this, many countries, such as the United States, have returned to using Salk’s vaccine as the standard method of childhood polio vaccination. In hindsight, it was fortunate that we had both the Salk and the Sabin vaccines. This is something to remember as we hope for a vaccine that can protect us from the COVID-19 disease.
The Race to a COVID-19 Vaccine
The human and economic carnage caused by the COVID-19 pandemic, the lack of effective therapies, and the realization that it would be difficult to acquire herd immunity through natural infection has led to many efforts to develop a vaccine. Here, we describe just two efforts as examples that we hope will illustrate the lightning speed with which COVID-19 vaccine development has proceeded.
Dan Barouch is a physician and a scientist at Harvard Medical School and the Ragon Institute in Boston. After finishing his education and postdoctoral training, he set up his own laboratory with the goal of developing molecular approaches to design vaccines that could halt global pandemics. His laboratory was primarily focused on developing an HIV vaccine using the adenovirus vectors that we described earlier. In 2007, Barouch and collaborators reported the creation of several such vectors. They inserted the genes corresponding to HIV proteins in one such vector, called Ad26, and clinical trials showed that the resulting vaccine was safe in humans and induced immune responses.
Barouch then launched a collaboration with the Johnson & Johnson (J&J) company to manufacture the HIV vaccine and perform a large clinical trial, efforts that are currently underway. In 2016, when the Zika epidemic was going on, Barouch’s lab inserted the genes of this virus into the Ad26 vector. Again with J&J, the vaccine was manufactured, and a clinical trial showed that just one dose of this vaccine resulted in neutralizing antibodies that were durable for a year. But, because Zika quickly waned in South America, a vaccine was no longer needed. Based on this work on Zika and HIV, Barouch and J&J established that the Ad26 vector was safe in humans and that millions of doses of a vaccine could be manufactured.
When the sequence of SARS-CoV-2 was made available on January 10, 2020, the Barouch laboratory was at its annual retreat. Because the sequence of the spike protein was distinct from other coronaviruses, the team realized that SARS-CoV-2 might cause a pandemic. On the evening of January 10, they started to design an Ad26-based vaccine that might protect against COVID-19. They focused on the spike protein, anticipating that neutralizing antibodies that could bind to its spike might be effective. In parallel, preparations were made for initiating studies in mice, monkeys, and ferrets. On January 25, Barouch called J&J, and four days later they had signed a collaboration agreement. J&J announced that they would invest $1 billion to make a billion doses of this vaccine if it proved successful in clinical trials. Animal tests subsequently showed that the vaccine elicited both antibody and T-cell responses. Clinical trials of this vaccine concept started in July 2020.
Moderna, a biotechnology company in Cambridge, Massachusetts, moved even faster. Moderna was established in 2010 and is focused on developing therapies and vaccines based on RNA delivery technologies. The SARS and MERS epidemics made clear that new coronaviruses could jump to humans, and were a serious threat. Scientists at Moderna had been studying how the new concept of RNA vaccines could be used to protect against such viruses. They found that a modified form of the RNA corresponding to the spike protein of MERS when encapsulated in a nanoparticle could elicit neutralizing antibodies to MERS in animals. Based on these studies, Moderna scientists were poised to help confront the COVID-19 pandemic.
Within 24 hours of the public release of the sequence of SARS-CoV-2, Moderna started work on creating an RNA vaccine that may protect against COVID-19. They quickly designed a modified form of the sequence of the RNA corresponding to the spike protein of SARS-CoV-2 and formulated a vaccine. While manufacturing an adenovirus-based vaccine takes some time, an RNA vaccine can be made in days to weeks. On March 16, in collaboration with the National Institutes of Health, Moderna started a phase I clinical trial. A press release shortly thereafter announced that the vaccine was safe in humans and could elicit antibodies against the virus’s spike. Phase III efficacy trials could be completed in the autumn of 2020.
Neither an RNA or an adenovirus vaccine has ever been licensed for human use. So, if either type of vaccine succeeds, it will be a major achievement. Since the technology to produce adenovirus-based vaccines is more mature, mass production may be easier than for RNA vaccines.
Many other ideas and concepts for developing a COVID-19 vaccine are being pursued. For example, Oxford University and the company AstraZeneca are developing a vaccine based on concepts similar to, but distinct from, the J&J vaccine. This vaccine is also being tested in humans. Many other companies around the world are developing vaccines based on DNA and RNA, as well as other technologies. A collaboration between Pfizer and BioNTech is just one additional example. It is unclear at this time whether any of the vaccine concepts being pursued will be efficacious and whether the vaccine-induced immunity will be durable. So, it is wonderful that many vaccine ideas are being pursued in parallel. As the story of polio vaccines shows, having many vaccine options available can be very helpful. For COVID-19, it is almost essential that many vaccine ideas be pursued. If the virus continues to spread, we will need to vaccinate billions of people around the world to establish herd immunity. Having several efficacious vaccines available will help achieve this goal.
Clinical trials for vaccines that may protect us from COVID-19 are moving forward at a phenomenal pace. Manufacturing processes and facilities to make enormous numbers of doses of different vaccine candidates are being built in advance of knowing whether a particular vaccine will work. Some of these investments may well be for naught. But these facilities are being developed and built so that manufacturing does not become a bottleneck for rapidly deploying a successful vaccine. It is estimated that roughly 5 billion doses of COVID-19 vaccines will need to be deployed across the globe. If a booster shot is required, this number will double. In addition to manufacturing the vaccine, enormous numbers of vials to store and transport vaccines and devices like syringes necessary to inject vaccines into people will be required. These are enormous manufacturing and logist
ical challenges that we will have to overcome. Indeed, we will learn a lot from efforts to stop the COVID-19 pandemic.
The Long Pursuit of a HIV Vaccine
The HIV virus was identified over 35 years ago. Intense research efforts and significant financial investment since then has not led to a successful vaccine. This experience has made some wonder whether a vaccine that can protect us from COVID-19 can be developed in the near future. From a vaccine design perspective, however, HIV and SARS-CoV-2 are very different viruses. SARS-CoV-2 (and its spike protein) is not mutating very much. This suggests that if the current vaccines being developed can elicit neutralizing antibodies they will likely be efficacious.
In contrast, HIV is a highly mutable virus that replicates very quickly in humans. More than a billion new virus particles are generated in a single infected person every day, and many have mutations. Most of the mutant viruses are dysfunctional. But some are not. Our immune system mounts robust antibody and T-cell responses upon HIV infection. But very soon, mutant viruses emerge that are functional and can evade this response. For example, antibodies are produced that can bind to virus particles with a particular spike protein and prevent them from infecting new cells. After a few cycles of virus replication, mutants with different spike proteins emerge. The previously efficacious antibodies can no longer bind to the new spikes. Similarly, strong T-cell responses are mounted to HLA-bound fragments of HIV proteins. But soon strains with mutations in these protein fragments emerge. Of course, new immune responses are then mounted, but the virus mutates again. This is the reason why no one infected with HIV has been definitively identified to have completely cleared HIV infection. This also explains why there is no efficacious vaccine yet.
Progress is being made, however, to address the challenge presented by HIV’s high mutability. Parts of the spike proteins of HIV do not mutate much. These regions need to stay the same for the virus to be able to infect human cells. If a vaccine could elicit antibodies that bind to these regions, it would prevent the vast majority of mutant strains of HIV from infecting our cells. Antibodies that can achieve this goal are called broadly neutralizing antibodies (bnAbs). Some infected persons do produce such antibodies, usually several years after infection, and not in large enough numbers to clear the infection. But their existence provides the proof of concept that the human immune system can generate bnAbs. Intense efforts are underway to develop vaccines that can elicit bnAbs.
The other HIV proteins also have regions that cannot mutate much. Interestingly, some combinations of mutations in HIV proteins cannot emerge without making the virus dysfunctional. If different killer T cells simultaneously attacked infected cells that displayed the regions where combinations of mutations are unviable, the virus would be trapped. The combination of mutations that could evade the T-cell responses would make the virus dysfunctional, and if the mutations did not emerge, the killer T cells would kill the infected cells. A small number of people, called elite controllers, can mount T-cell responses that target the mutational vulnerabilities of HIV. They do not eradicate the virus from the body (with perhaps the exception of one very recently reported case), but virus levels are very low in these people and so they do not proceed to the disease, or AIDS. Intense efforts are underway to design vaccines that can elicit T-cell responses that resemble those mounted by elite controllers.
Perhaps the work being done to develop vaccines that can protect against diverse HIV mutant strains will one day be useful for designing a vaccine that can protect us from all coronaviruses, past, present, and future.
Vaccine Safety
For most of us, the suffering caused by diseases like smallpox, polio, mumps, rubella, and measles is just something we read about in history books. This is because of the enormous success of vaccines in protecting the human population from many infectious disease-causing viruses. At the same time, fears that vaccines might cause disease have also been voiced. Recall from chapter 1 that only after variolation was shown to be safe in some prisoners and children did the Princess of Wales allow her children to be variolated. Similarly, in the early twentieth century, Henning Jacobson in Boston refused to be vaccinated against smallpox because he was concerned that the vaccine might make him sick. Such fears are not unreasonable because vaccination is a medical procedure performed on healthy persons, and involves injecting a foreign substance into an individual. But, over the years, vaccination has proven to be remarkably safe.
Early on, because of a manufacturing error, a batch of the Salk polio vaccine was not fully inactivated, and unfortunately resulted in polio infections. But modern manufacturing processes and strict regulation of GMP facilities make such errors unlikely today. In the United States, the FDA carefully reviews all data from preclinical and clinical trials before licensing a new vaccine for human use. The FDA and the CDC maintain the Vaccine Adverse Event Reporting System, and the CDC maintains the Vaccine Safety Datalink. These entities allow for careful, real-time tracking of the safety of vaccines. In the United States, there is also the National Vaccine Injury Compensation Program, which receives reports of adverse effects of vaccines. Between 2006 and 2013, for every million vaccine doses that were administered, there was roughly one report of an adverse reaction. Even the adverse effects due to mutations in Sabin’s polio vaccine that have led to discontinuing its use in some places occur in only about one in a million vaccinated people.
An influenza vaccine in 1976 was linked to Guillain-Barre syndrome, which is a disease where the immune system attacks nerves. While this is scary, it now appears that such adverse events may be associated with viral infections and not the vaccine. Recent concerns about a connection between vaccination and autism are rooted in a 1998 paper in the journal Lancet, published by Andrew Wakefield and coworkers. In this work, the authors claimed that there was a connection between MMR vaccination and a “pervasive developmental disorder.” Extensive follow-up studies have completely discredited this work, and the paper was retracted.
Adverse events can and do occur after vaccination, but these are rare events. Given this rarity, and the enormous benefit derived from protecting society from infectious diseases, it seems clear that vaccines have been a boon for humanity. Furthermore, noncompliance with vaccination programs puts vulnerable people in society at risk. The COVID-19 pandemic has made vivid the traumatic conditions that would prevail in a world without vaccines.
Epilogue
Since time immemorial, we have been at war with viruses. Innovations such as agriculture and the industrial revolution have improved the human condition. But these advances also led us to adopt lifestyles that favored the spread of highly contagious, infectious disease–causing viruses. We have largely been winning the war with these viruses because our immune systems can usually vanquish most viral infections, and because of technological innovations that have helped thwart the risk of contagion. These technological innovations include better sanitation, vaccines, and therapeutics. But we remain vulnerable for periods of time without protection when a new lethal virus emerges. Such events are inevitable because many viruses related to those that afflict us are also circulating in animals. Given the malleability of the genomes of RNA viruses in particular, new viruses can emerge that jump from animals to humans. When this happens, no one in the human population has protective immunity to it. If this virus is highly infectious and moderately lethal, devastating global pandemics can result.
The COVID-19 pandemic is a reminder that infectious disease–causing viruses are an existential threat to humanity. The costs of this pandemic have been enormous in terms of both human and economic damage. Almost a million people have died worldwide, tens of millions have lost their livelihoods, and global economic losses are measured in the tens of trillions of dollars. Governments are scrambling to respond, in many cases effectively limiting the death toll, but along the way creating a fiscal debt that will be borne by generations to come.
It doesn’t have to be this way again. Informed by our histor
y of battles with viruses, and the recent lessons learned from the COVID-19 pandemic, we need to create an integrated system of technologies that will help us prepare to respond more rapidly and effectively the next time, thereby saving millions of lives and trillions of dollars. A focused effort to create such a system will help us win the future by preparing for the “enemy” before it arrives.
We envision a future where a set of six interlinked technologies, developed based on rigorous and interdisciplinary scientific advances and informed by ethics and considerations of human well-being, can create a more pandemic-resilient world.
Early diagnosis and ongoing surveillance It is absolutely essential that we be prepared to test for a new virus on a large scale. Based on existing advances in synthetic biology, nanotechnology, biosensing, and device engineering, we can create diagnostic tests that are reliable, portable, user-friendly, and minimally invasive. These diagnostic platforms will have interchangeable parts that can be rapidly adapted to test for a new virus or corresponding antibodies. With tools like this, we will be able to rapidly survey a large proportion of the population to accurately measure infection rate, monitor the spread of the infection in real time, classify potential patients to prompt appropriate follow-up actions, and help craft data-driven approaches to mitigate the spread of disease. Ongoing randomized testing of the population in a noninvasive and cost-effective manner will also allow real-time surveillance of new disease outbreaks and the fraction of people who have become immune.
The development of new virus surveillance and tracking tools will also pose many new ethical questions. Scientists, engineers, and public leaders will have to work very closely with humanists and social scientists so that the tools that help us fight pandemics do not do irreparable damage to free societies around the world. It is our hope that readers of this book who are humanists and social scientists will be inspired to be willing to work closely with scientists and engineers toward this end.
Viruses, Pandemics, and Immunity Page 15