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The International Society for Vaccines is an organization that engages, supports, and sustains the professional goals of a diverse membership in all areas relevant to vaccines - 2019 ISV Annual Congress


Title:Challenges in developing vaccines against emerging virus infections

By - Adolfo García-Sastre (ISV President), Icahn School of Medicine at Mount Sinai

While vaccination is the best way to prevent infectious diseases, development of emerging virus vaccines represents a major challenge. The unpredictable nature of emerging viruses, such as MERS, Ebola or pandemic influenza, makes impossible to conduct efficacy trials, as the location and magnitude of the outbreaks, as well as of the specific virus strain causing it, are extremely difficult if not impossible to predict before their emergence. On the other hand, once an outbreak emerges, there is no time to conduct controlled efficacy trails in order to deploy an effective vaccine on time to contain the outbreak.

The 2009 pandemic influenza virus provided with one example of the problems associated with vaccines against newly emerging viruses. Such influenza virus originated from a swine H1N1 influenza virus strain and it was detected in humans only after it was already widely disseminated in Mexico. The outbreak extended quickly to US and the rest of the world, and by the time a pandemic H1N1 vaccine was available and started to be used, the pandemic outbreak had already reached peak infections, and influenza infection cases were in decline. Thus, the vaccine was unable to impact the magnitude and severity of the first wave of infections. Fortunately, this pandemic influenza virus did not cause a large number of severe and lethal human infections, as in the case of previous influenza virus pandemics. Nevertheless, many human lives were lost that could have been prevented by vaccination, if a vaccine would have been available at earlier times.

The lack of a timely vaccine has also hampered the control of the recent ebolavirus outbreak, which is still ongoing although at a lower magnitude, and has devastated the public health system and the economy of several Central West African countries, with more than 10,000 human lives claimed. Previous ebolavirus outbreaks were characterized by high mortality but small number of geographically confined humans cases in remote and underpopulated areas in Central Africa. The virus is thought to jump from a bat reservoir into humans where it undergoes human to human transmission mainly due to contact with infectious body fluids. While ebolavirus human transmission is quite ineffective as compared to other acute and established human virus infections, it was generally accepted that sooner or later, an outbreak would reach one or more larger cities in Africa, where containment would be more difficult and the number of cases would be several orders of magnitude higher. Despite that, the development of ebolavirus vaccines has been a very slow process, due to low priority and to the challenges associated with licensing a vaccine with only animal model data in the absence of (impossible to conduct unless a major outbreak occurs) efficacy trials in humans. The recent outbreak, while boosting the speed and resources put into ebolavirus vaccines, has not been contained by vaccination, as vaccines with proven efficacy in animal models were not available for human use on time.

MERS coronavirus infections in humans have first been described in 2012. This virus in now known to be endemic in several Middle East countries, and human infections likely involves camel to human and human-to-human transmission. MERS disease is a clear reminder of the SARS coronavirus outbreak, both diseases caused by a zoonotic coronavirus that induces acute respiratory syndrome infections in humans, and with the ability to spread from human to human. Although concerns were raised about the potential impact of this virus in humans in the near future, MERS vaccine development has been impaired by the lack of appropriate resources given to this, and the constrains associated with the development of animal models and the lack of a clear path to licensure in the absence of clinical human efficacy trials, which are not possible to be conducted due to the low number of current human infections. The recent outbreak of imported MERS in Korea in the absence of a human MERS vaccine reminded us once more of what these emerging viruses can cause and how much time is lagging behind effective vaccines that can contain these outbreaks.

Pandemic influenza, Ebola and MERS are just three examples of predictable outbreaks for which experimental preclinical vaccines are available, but which lack of a rapid path to approval for human use, a step that is necessary for vaccines to make and impact in future and potentially more devastating outbreaks. Let’s not wait for one more outbreak to realize the need for a different strategy that allows for a more rapid deployment of vaccines against emerging and zoonotic viruses.


By - Rebekah Schrepfer

Buckle up for a Mostly Sensible opinion of the Vaccine Wars. There are really few debates out there that have caused such an uproar and influenced decisions about such a personal part of our lives, namely, our children. There is so much to weed through in this debate of whether ‘To Vaccinate, or Not To Vaccinate’ your children. Since the Pro-Vaccine Movement seems to have gotten behind the Anti-Vaccine Movement in spreading their side of the issue on the Internet and social media, I wanted to just tell my point of view that vaccines are safe for the vast majority of our population, even necessary in this age of global travel, and why.

I’ve learned a lot from the reading that I’ve done. And given the deluge of information out there against the use of vaccines, I’m actually surprised to find myself on the Pro-Vax side of things. Before I was married, I did tend to lean toward the belief that all-natural is generally going to be better. Why take or eat something synthetic when natural can be just as effective (so they say). Keep things the way God created them to be. Quit messing with “nature.” And given all the stories out there and campaigns to discourage folks from vaccinating their kids, I was open to the idea of not vaccinating my own children when the time came. After all, I had taken advantage of some homeopathic treatments before with some success.

But being the Mostly Sensible person I am, I didn’t want to take anything at face-value, and I determined to find out more about the issue. Having been vaccinated myself, my husband as well, without problems it seemed reasonable to let my children be vaccinated. I did opt out of the optional vaccines, and I also did a bit of research into the MMR vaccine and the autism scare before those were given to my kids. Being confident that the vaccine was safe as you’ll see below, I did not opt out of that one. That was the beginning of my skepticism in the Anti-Vax Movement. So I did some more reading.

Admittedly, I have not delved too deeply into the plethora of materials available. That would be a full-time job! But what I have learned, has led me to be very confident that immunizations are safe, and the benefits outweigh the relatively small risks. I hope you will see what I mean. Here are the reasons why my children are immunized.


By - Clarisa B Palatnik de Sousa

Vaccination is the most effective method of preventing infectious diseases and is largely responsible for the worldwide eradication of smallpox and the restriction of diseases such as polio, measles, and tetanus from much of the world.

In USA, where population had access to vaccines and antibiotics, during the first 8 decades of the XX century, the infectious disease mortality rate declined substantially. A total of 797 deaths per 100,000 was recorded in 1900 and only 36 per 100,000 in 1980, consistent with the concept of epidemiological transition from an age of pestilence and famine to an age of degenerative diseases. Pneumonia, Influenza and Tuberculosis were responsible for the largest number of infectious diseases deaths throughout the century. However, the emergence of AIDS and tuberculosis demonstrated that gain against infectious diseases were not definitive. In high-income countries, 70% of deaths are due to chronic diseases, among people aged 70 years and older.

The global burden of tuberculosis remains however enormous in Southeast Asia, Sub-Saharan Africa and Eastern Europe, mainly because of the poor control and high rates of M. tuberculosis and HIV co-infection in some African countries. Every year there are 350–500 million cases of malaria, with 1 million fatalities (90 percent in Africa). In low-income countries, nearly 40% of deaths are among children and only 20% among people aged 70 years and older. People predominantly die of lower respiratory infections, HIV/AIDS, diarrheal diseases, malaria and tuberculosis.

Several important problems impeded us from defeating infectious diseases. Among them, we can consider: 1) vaccine R&D funded at 10% of which goes to research in therapies 10; 2) the increased standards of safety regulations applied to vaccines, that promoted the evolution to recombinant or synthetic vaccines, which are less immunogenic and demand a more sophisticated industrial technology; 3) the lack of vaccines based on universal antigens that will exert cross-protection to the prevalent variables of all continents; 4) the lack of vaccines based on conserved antigens that would not demand annual revaccination and 5) the extensive numbers of Phase II-IIb and Phase III trials required before licensing a vaccine. In addition, due to the recent global economic crisis, vaccine companies of USA and Europe consider interrupting the fabrication of preventive vaccines and showing more interest in the development of therapeutic vaccines or drugs, which are more profitable.

On the other hand, in developing countries such as Brazil, Argentina and others, Public Health programs of vaccinations rely on the partial or complete production of vaccines by non-profitable Public Institutions. Although the government might buy vaccines from foreigner companies, a national immunization program and a plan to achieve self-sufficiency in vaccine production through local institutions exists. The success of control of infectious diseases by vaccinations depends not only on the free distribution of vaccine by the government institutions but also in the obligatory condition of vaccination. In contrast, the non-obligatory condition of anti-rabies canine vaccination in Europe, and the lack of control for anti-rabies vaccination for exported animals allowed the recent detection of canine rabies, in Britain caused by infected dogs being exported from Bulgaria.

The future success in the worldwide control of infectious diseases by preventive vaccination however, might depend on the strengthening of the model adopted by developing countries, which involves the obligatory, gratuitous governmental distribution of vaccines produced by Public Heath non-profit institutions.


Title - Making “BioBetter Vaccines: progress on the influenza front.

By - Annie De Groot (ISV Fellow) and Lenny Moise – University of Rhode Island and Epivax

Have you ever had a sentence stuck in your head? One sentence that I can’t forget was uttered by Robin Robinson at a recent convening of vaccinologists (Vaccine Technologies V, Playa del Carmen, Mexico, 2014). He said “we’re making great pro- gress on building vaccine manufacturing capacity in the US, and we are also making progress developing methods to accel- erate vaccine production, but we are not making good progress on vaccine efficacy.”

The underwhelming performance of H3N2 seasonal influenza vaccine for the 2014-2015 flu season is a case in point. Is it any surprise that public confidence in influenza vaccination is at an all time low? And from the pandemic perspective, poor vaccine efficacy can be even more worrisome. As of this writing, the H7N9 strain that emerged in China in 2013 still holds signifi- cant pandemic potential, and, as with H3N2, H7N9 vaccines appear to be underperforming. , Both the H3N2 and H7N9 strains present unique challenges to vaccinologists. Anti-H7 antibody responses are significantly delayed and exhibit low avidity, in comparison with antibodies generated following seasonal influenza vaccination and infec- tion. Responses to H3N2 have also been reported to decrease with additional immunizations. Are these problems due to the existing standard designs for flu vaccines? Is it time for change? A number of exciting new approaches have been pro- posed to improve the immunogenicity of vaccines and ISV re- searchers are at the forefront of influenza research.

For example, the team at EpiVax, working with Rui Liu at the University of Rhode Island, have discovered that H7N9 con- tains fewer T cell epitopes and some epitopes stimulate regula- tory T cells (Tregs) that may help the virus evade effector re- sponses needed for protection. Researchers at the Institute for Immunology and Informatics (University of Rhode Island) and EpiVax are seeking out, and finding, Treg epitopes in other pathogens, including HIV, Hepatitis C Virus, and parasites.

Can anything be done to fix the problem? Yes, as it turns out. Using methods that were honed on biologics, for the purpose of ‘deimmunization’ (removal of T effector epitopes), these vac- cine design teams have been modifying H7N9 sequences so as to remove Treg epitopes. With Manobu Ato and Yoshimasa Takahashi at National Institute for Infectious Diseases in Japan, the researchers are observing improved antibody titers. They are definitely not standing around with their hands in their pockets!

Stay tuned, as vaccine developers begin to outsmart viruses that have adapted to humans, so as to develop “biobetter vaccines” in response to global (and governmental) demands.


Title - Vaccines in our Genes

By - Ray Spier, ISV Fellow

It has taken 35 years to arrive at a point which I envisaged when I was working on the production of Foot-and-Mouth Disease (FMD) vaccines at the, then, Animal Virus Research Institute at Pirbright, U.K.. Just following the publication of the papers showing that genetic engineering was practicable, it becomes obvious that to genetically engineer a cow to systemically produce its own vaccine to FMD was on the cards. The open option was to produce 7 vaccines (one for each type of virus) from 7 antibody genes that had been introduced into the genome. Later this approach would be better defined by discovering a single gene that would produce a cross-protective (broadly neutralising) antibody that would neutralise all 7 virus types.

A publication in this area in 1996 (1) evidenced the practicability of immunoprophylaxis by genetic immunisation. Since then the method (CRISPR-Cas9) for inserting foreign genes into specific loci in the genome have been developed (2) and numerous targets for this technique have been assayed in animal models (mice and monkeys) with many successful immunisations. At the time of this writing the targeted human diseases are HIV, Malaria, Influenza, Ebola and Hepatitis where some safety testing in humans is under way. (Carl Zimmer: Redesigning the body to fend off disease. International New York Times, 10/03/15, page 1). Additionally the technique has been defined as “Immunoprophylaxis by Gene Transfer” (IGT). To fully develop the potential of this technique the genes to be transferred should code for antibody molecules that can cross-neutralise the neutralisation epitopes of all the disease causing organisms, their types and subtypes.

The problems with the application of this technique may not be in the area of successful immunizations but rather in the area of regulation and ethics. Various conventions have been promulgated that forbid the genetic transformation of the human genome. This has been relaxed in some cases (the single gene disease of Cystic Fibrosis) but the regulations do not allow a genetic transformation that might be incorporated into the germ cells and become part of the germ line of the individual. This regulation may also be relaxed for some hereditary diseases such a Huntington’s Chorea.

There are several other issues connected to IGT such as the effect of having a number of different antibody molecules secreted into the blood stream without any control mechanism preventing overproduction and self-reactions to the influx of the additional components of the phenotype. A second possible scenario is how might we respond to a mistake in a gene insert. If the new gene interacts with other elements in the genome with harmful consequences how would we deal with the person and then that person as a potential progenitor of other disadvantaged persons in the future?

IGT is a powerful tool. As with all tools they can be used to bring benefits and to cause harms. Our job is to examine what we can do with this new tool, proceeding carefully and cautiously - but proceeding nonetheless.

(1) Immunoprophylaxis of allergen−induced immunoglobulin E synthesis and airway hyperresponsiveness in vivo by genetic immunization; Ching-Hsiang Hsu¬, Kaw-Yan Chua¬, Mi-Hua Tao, Yih-Loong Lai, Heuy-Dong Wu, Shau-Ku Huang & Kue-Hsiung Hsieh; Nature Medicine 2, 540 - 544 (1996) doi:10.1038/nm0596-540

(2) The new frontier of genome engineering with CRISPR-Cas9; Jennifer A Doudna and Emanuelle Charpentier; Science 346 No6213 13pp 2014 DOI 10.1126/science 1258096

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