Vaccines and global stability: achievements and challenges

The prevention of infectious diseases by vaccination has a profound effect on the stability of our society. Close contact between individuals facilitates the transfer of infectious agents, and with more than 50% of the global population living in cities, it is difficult to escape from those contacts [1]. Vaccines and antibiotics are the weapons to treat or prevent lethal infectious diseases. The introduction of vaccination has led to an enormous reduction in human suffering and an increase in life expectancy. At the same time, we have become increasingly dependent on vaccination. This is not a problem as long as there is a smooth and continuous supply of the necessary vaccines. However, such a supply does not come automatically. It requires close collaboration of the public sector, which should be in the lead, the profit-driven pharmaceutical industry and academia, the source of scientific innovation.

Human civilization & microbial evolution

Before addressing the challenges to make this collaboration happen, I want to underpin my thesis that a society cannot function without vaccination by going back to the origin of the human society and to life before vaccination. Mankind started out on earth approximately 200,000 years ago as hunters and later as a hunter–gatherers. Sedentary life in small settlements began 11,000 years ago. Small villages grew into cities. Living together had its consequences for the evolution of infectious agents. Early humans got infected by infectious agents of animals, such as the rabies virus or the anthrax bacterium, but there was no human-to-human transmission. Only after larger human settlements developed, did infectious diseases specific to humans, such as measles, smallpox and rubella, develop [2].

As cities became bigger and were connected by trade routes, infectious diseases became an increasing problem. In particular, the plague and smallpox caused many fatalities. Even in the 20th Century, approximately half a billion people died from smallpox. In the absence of any knowledge on the nature of infectious agents, our ancestors came up with quarantine and isolation. Ships with infected individuals on board had to wait for 40 days outside the harbor before debarking. On land, isolation was more difficult to enforce and, as we can read in the Decameron from Giovanni Boccaccio, approximately half of the citizens of Florence died from the plague that hit the city in 1384. In our present global society, with 2 billion airline passengers per year, quarantine is no longer an option.

After Jenner discovered that vaccination was effective in the prevention of smallpox (until then the cause of approximately 10% of all deaths), this method became widespread in Europe and its colonies, and remained so until 1979, the year of the eradication of smallpox. We can hardly imagine how life was before vaccination. To give just one example to put a face on the suffering, Rembrandt van Rijn, the famous Dutch painter, was born in 1607, married twice and lost both wives to infectious diseases, the first one at the age of 27 years. Of his five children, three died shortly after birth, presumably from an infectious disease. His son Titus died from the plague at age 27. The sorrow of these losses is visible on the face of Rembrandt in the series of his self-portraits.

Rolling out vaccination programs

Life without vaccination is still a reality in some developing countries but tremendous progress has been made since 1974, after the start of the Expanded Program in Immunization of the WHO. Thanks to the generous support by funds, such as the Global Alliance for Vaccines and Immunization, supported by Bill and Melinda Gates, money has also become available for the poorest countries that are unable to pay for the vaccines themselves. Nevertheless, effective vaccines against the three most important diseases in these countries, HIV/AIDS, tuberculosis and malaria, are still lacking. Developing these vaccines remains a high priority, not only from a medical point of view, but also as a boost to the economy of these countries. Economic analyses show that vaccination does more than increasing the health status. Vaccination and the resulting better health also leads to more profit from education and, thereby, to higher IQs and more wealth [3].

Managing national immunization programs

All industrialized countries have developed vaccination programs to protect their citizens against serious diseases, such as diphtheria, tetanus, pertussis, measles and poliomyelitis. Later on, vaccination against mumps, rubella, Haemophilus influenzae type b infections and hepatitis B were developed. In more recent years, vaccinations against meningococci C, pneumococci, varicella, rotavirus and human papillomavirus were introduced. More vaccine candidates for national immunization programs (NIPs) are in the pipeline. In addition, vaccines targeting adults (pertussis boosters) and the elderly (herpes zoster) are now available. The decision to introduce a vaccine into the NIP is usually taken at the national level. Cost–effectiveness expressed as the amount of money required to gain a life year or a quality-adjusted life year (QALY) is invariably a selection criterion, but country by country there are additional criteria. Nowadays, individual countries (at least in Europe) carry out duplicate investigations to decide whether a new vaccine should be included in the NIP or not. Clearly, more collaboration between countries would save effort and time.

Vaccine development & production

Vaccine development is a lengthy and expensive process. It takes on average 10 years and costs up to €1 billion [4]. Only two out of every ten attempts to develop a vaccine are successful. Vaccine development has distinct phases. The start is fundamental research into the infection, the infectious agent and the vaccine antigens that could elicit protection. These antigens are then tested in animals for proof of principle of protection and for safety. When the results of this phase are satisfactory, the vaccine goes into the phase of clinical development and licensing. This latter phase is responsible for approximately 7.5 years of the development time of a vaccine and 80% of the costs.

Vaccine production & vaccine shortages

Owing to mergers in the pharmaceutical industry, there are presently only five big vaccine producers left. Together, they produce 90% of the vaccines for industrialized countries. Developing countries, where approximately 80% of the global population live, have their own producers. These producers also supply vaccines outside their boundaries via organizations such as the United Nations Children’s Fund (UNICEF) or the Pan American Health Organization (PAHO). In 2007, 70% of all PAHO vaccines came from these producers [5].

Existing excess production capacity for vaccines has disappeared. Together with the inevitable failures in the biological production processes needed for vaccine production, this results in occasional vaccine shortages. The USA is very transparent regarding these shortages. A special website of the US CDC summarizes the current situation and gives suggestions regarding how to cope [101]. Also, in Europe, vaccine shortages lead to stagnations in the NIPs of countries.

A bigger problem is the timely vaccine supply against agents of bioterrorism, such as smallpox and anthrax, and emerging infections, such as pandemic influenza and SARS. There are commercial, political and scientific barriers in vaccine supply. I will go into more depth on the scientific aspects. The commercial problem is that the development and production of vaccines for which there is no lasting demand is unattractive, and therefore not a priority, for the established pharmaceutical industry. Usually only biotech companies will be interested but these are not always able to deliver, as the US government experienced in the procurement of anthrax vaccine [6].

Challenge to develop & produce vaccines against completely new infectious diseases

Although the aforementioned vaccine shortages are worrying for a society dependent on vaccines, they are not the biggest challenge. That is undoubtedly the development and production of vaccines against completely new diseases, such as SARS. The World Health Report 2007, entitled ‘A safer future: global health security in the 21st Century’ was devoted to emerging infections [7]. The report summarizes that since the 1970s, 39 new infectious diseases have arisen, approximately one per year, and it concludes: “It would be extremely naive and complacent to assume that there will be not another disease like AIDS, another Ebola or another SARS, sooner or later”. Looking more closely at the new infections of the last few years demonstrates that the most dangerous ones were caused by mutants of animal viruses. Owing to the mutations, these viruses became able to infect humans, followed by human-to-human transmission. That is exactly what happened with SARS [8]. Fortunately, SARS was contained close to the source, but the consequences could have been much worse [9].

Another new, serious, infectious disease would be a direct threat to our civilization and economy as it functions now. With a development time for a vaccine of 10 years we have no quick fix for such a threat. This article is also a call for action – action comparable with the preparation for war. This would have to be a high-tech war taking advantage of scientific innovation of the past and incorporating technologies that have yet to be developed. A program targeting these new innovations has to be set up.

There are three possible lines of defense:

• • Small molecules with antiviral properties

• • The revival of serum therapy

• • Revolutionizing vaccine development, comparable with the revolution from transistor to chip

The first line of defense could be pursued more rigorously. A good example is the Vizier project of the EU, which aims to identify potential new drug targets against RNA viruses [102]. However, for sustainable mass medication with antiviral drugs, it will be necessary to use mixtures of at least three different compounds, targeting different viral functions. Otherwise, resistance may develop rapidly.

There are now good reasons to reconsider passive immunization, with antibodies that neutralize viruses, for the control of viral diseases. The problems connected to the use of animal sera have been solved by the availability of synthetically produced human antibodies. In addition, the development time is much shorter than for vaccines, as was proven by the development within a short time of antibodies against the SARS virus [10]. Production of antibodies in mammalian cell lines has become much more efficient. Yields have gone up by a factor of 1000 in the past years. Therefore, the costs of producing the 2 g of antibodies that would be required to treat an adult have gone down to approximately €100. However, the facilities required to produce sufficient amounts of antibody to treat, for example, 10% (49.7 million people) of the population of the 27 EU member states are not in place. Production in plant cells may be the solution. Yields are high and initial problems with shorter half-lifes in man due to difference in glycosylation seem to be solvable [11].

The third approach is a tremendous challenge! However, the benefits of this approach would be that development times of vaccines and other drugs will go down. Since approximately 80% of the time and the budget for vaccine development is spent on clinical development, this would be the place to look for radical innovations leading to shortened and less costly timelines. The present clinical studies all focus on end points, usually antibody titers against the infection and for efficacy and adverse effects recorded by the recipients of the vaccines or their parents. Some developments that could contribute to this revolution are already visible. The first is the use of better animal models. It does not make sense to continue to work with an animal model that has no predictive value for humans. An insightful overview summarizes the criteria for the selection of appropriate animal models [12]. Combining animal models with advanced imaging techniques, such as PET–MRI, will generate much more data with fewer animals [13]. The second development is to use cDNA microarray technology. This will advance both the prediction of adverse effects of vaccines and the detection of protective immune responses. Some pioneering studies have already shown the value of this approach [14–17].

In summary, we need to develop better medicines to protect our society against emerging infections. There are sufficient scientific and technological possibilities to develop and produce these medicines. Currently, national and supranational task forces to do this are lacking. This is surprising in view of the dire consequences that can be expected from future emerging infections.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.