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How are Vaccines Made?

Vaccines for Pandemic Threats

Last update 10 January 2018

Vaccination will likely be part of a multi-faceted public health response to the future emergence of a pandemic illness. In addition to other measures designed to respond to and control a pandemic, such as surveillance, communication plans, quarantine, and disease treatment, deployment of effective vaccines has the potential to protect lives and limit disease spread. Not all disease threats, however, have a corresponding vaccine, and for those that do, there are significant challenges to their successful use in a pandemic.



Pandemic diseases (epidemic diseases that spread over a wide region), have swept through human populations for millennia, causing hundreds of millions of deaths. Historians estimate that bubonic plague, also known as the Black Death, killed between 25 and 75 million people in Europe in the 1300s. Recurring waves of the illness swept through Europe until its last major appearance in England in the 1660s. Smallpox took an even higher global toll over thousands of years, until it was declared eradicated in 1980.

The 1918-19 influenza pandemic killed an estimated 40-70 million people worldwide. Other, less severe, pandemic influenzas emerged in 1957-58, 1968, and 2009. In the latter three cases, researchers developed influenza vaccines targeted specifically to the circulating virus, though experts disagree about how effectively the vaccines curtailed disease spread. Bird flu, an H5N1 influenza that mainly infects poultry, began to infect humans in 2003 and has a high case fatality rate, but the virus has not adapted to spread between people. Public health authorities remain vigilant about tracking H5N1 in case the virus begins to be transmissible among humans. The U.S. government has stockpiled an H5N1 vaccine, though it is not certain that the vaccine will be effective against new forms of H5N1.

Other illnesses of current concern that could threaten the global population include Severe Acute Respiratory Syndrome (SARS). SARS, caused by a coronavirus, is an epidemic disease that seemed on the brink of pandemic in the early 2000s. It spread rapidly from its origin in Asia in 2002-2003 to Europe and the Americas before the outbreak was contained. It resulted in 8,098 reported illnesses and 774 deaths. Since the threat of SARS faded in 2004, no new cases have been reported. Several vaccines for SARS are being tested in animals and are in an early phase of human research should SARS re-emerge.

All of these pandemic threats can be characterized as emerging infectious diseases—diseases that have never before been recognized, such as SARS or new pandemic influenza strains—or re-emerging infectious diseases—diseases that have been long recognized but that are occurring in a new form or in a new location, such as the evolution of drug-resistant tuberculosis and the appearance of dengue fever in Florida. The National Institute of Allergy and Infectious Diseases maintains this 

A challenge in responding to pandemic diseases is that vaccines may not exist for them or that, especially in the case of influenza viruses, existing vaccines may not be effective against them. Though production methods and infrastructure for influenza vaccines are well established, each new influenza strain requires a new vaccine. Thus, any new pandemic influenza vaccine will take about 4-6 months to produce in large quantity. For other newly emerging threats without licensed vaccines, such as SARS, Marburg virus, Nipah virus, and the like, the time required to develop and produce a safe, effective vaccine is unknown and would depend on the nature of the threat and the state of current vaccine research for that threat. In almost all cases, several months would be needed to respond with the first doses of vaccines. Until a safe, effective vaccine were ready, other public health and medical measures, such as social distancing, quarantine, and use of anti-viral medications, would need to be employed to try to limit disease spread.


The Players: Who Is Involved in Emergency Vaccine Production and Response?

A variety of U.S. federal, state, and local agencies are involved in public health emergency preparedness and response. The U.S. Congress funds the Centers for Disease Control and Preventions Office of Public Health Preparedness and Response (PHPR) to build and strengthen national preparedness for public health emergencies caused by natural, accidental, or intentional events. Part of the CDC’s funding supports the Strategic National Stockpile, which manages stores of vaccines and drugs that may be deployed in national emergencies.

The U.S. Department of Health and Human Services (HHS) includes several offices involved in pandemic and bioterror response. The Office of the Assistant Secretary for Preparedness and Response (ASPR) was created after Hurricane Katrina and is responsible for leadership in prevention, preparation, and response to the adverse health effects of public health emergencies and disasters. ASPR conducts research, builds federal emergency medical operational capabilities. Within ASPR, The Biomedical Advanced Research and Development Authority (BARDA) is responsible for the development and purchase of the necessary vaccines, drugs, therapies, and diagnostic tools for public health medical emergencies.

State and local health departments, as well as public and private hospitals and local law enforcement agencies, would also be involved in responding to a pandemic public health emergency. Their roles are outlined in national response plans as well as delineated by organization-specific plans.


Role of the Food and Drug Administration

The U.S. FDA is involved in establishing a research agenda pandemic response, and it controls the pathway to licensure for vaccines, treatments, diagnostic tests, and other tools for responding to biological threats. The regulatory requirements for licensure of a vaccine are complex and apply to a multi-step process of safety, immunogenicity, efficacy testing, and post-licensure surveillance. (See the article to read about this non-emergency approval process.)

In situations when a new vaccine is needed quickly, the FDA has developed alternative pathways to licensure. One is an accelerated pathway to approval that might apply in the case of a life-threatening disease when a new process will produce a vaccine with meaningful therapeutic benefit over existing options. In other, more drastic threats, the so-called animal rule might be used—if research toward a vaccine or treatment would necessitate exposing humans to a toxic threat, then animal studies may be sufficient for approval. To date, these two rapid pathways have not been invoked for vaccines. More information is available at the FDA’s .

U.S. Emergency Use Authorization (EUA) is an option in pandemic response. After a declaration of emergency by the Department of Health and Human Services secretary, this program allows for use of an unapproved medical product (or a product that has been approved but not for the specific use applicable to the situation at hand) that is the best available treatment or prevention for the threat in question. EUAs were issued for antiviral treatments, a respirator, and a PCR diagnostic test during the 2009 A/H1N1 pandemic.


Vaccine Response to Pandemic Threat

In all pandemic situations in which a vaccine is available or potentially available, a large supply of vaccine would be necessary and would be needed quickly. Currently, the U.S. Strategic National Stockpile includes several types of influenza vaccines, including an H5N1 vaccine. The stockpile also holds millions of doses of other vaccines, antibodies, antiviral medications and other medical supplies. Should any of these stockpiled vaccines directly relate to an emerging pandemic, they would be deployed. But chances are that an emerging pandemic illness will require a new vaccine.

In the case of an influenza pandemic, existing vaccines would likely be ineffective against a radically new strain. Developing and globally distributing a new pandemic influenza vaccine will likely take 4-6 months (4 months to produce first doses of vaccine, and 6 months to produce enough to give to a large number of people), even while mathematical models demonstrate that pandemic influenza could spread globally within 6 months.

Another complicating factor to pandemic influenza vaccine production involves how the vaccine is made. Since the 1940s, seasonal and pandemic influenza vaccines have been produced in chicken eggs. The virus is introduced in the allantoic fluid of the fertilized egg (this is the fluid that bathes the embryo and yolk sac), and it replicates in the membrane surround the fluid. After about three days, the virus-containing fluid is harvested from each egg, and the rest of the manufacturing process proceeds. Dependence on egg-based vaccine production is, however, problematic even with non-pandemic seasonal influenza vaccine. First, eggs must be available in large quantities when vaccine production is to begin. Any disruption in egg supply – such as disease affecting chickens, or bad weather interfering with the shipping of eggs – can mean a delay in vaccine production. Second, some influenza strains grow more slowly or less robustly than others, which can result in delays or in lower yields of vaccine virus from each egg. Third, it is possible that some viral vaccine strains, given the origin of some influenza viruses in birds, may be toxic to eggs. In that case, egg-based influenza vaccine production methods would be useless.

Production capacity is another limitation to deployment of pandemic influenza vaccine. Current global capacity for pandemic influenza vaccine production is less than 3 billion doses per year, far short of the 7 billion doses that would be needed for universal coverage.

To address some of these problems with egg-based vaccine production, some pharmaceutical companies are attempting to eliminate eggs from the process altogether. Novartis produces influenza vaccine from virus cultivated in cells derived from canine kidney cells (see the on this vaccine). Protein Sciences Corporation produces influenza vaccine using recombinant DNA technology and an insect virus system (see the ). Other companies are developing influenza vaccine produced from different types of cell lines.

Given that it takes roughly the same amount of time for influenza virus to replicate in eggs and in cell culture, shifting to cell culture will not necessarily speed up this phase of production. However, using cell culture technology will eliminate the lead time necessary to secure fertilized eggs for vaccine production and will reduce some of the variables related to the quantity of vaccine virus achieved with eggs. Additionally, egg-based influenza vaccine production requires a step in which the influenza virus is altered so that it reproduces well in eggs. If cell-based manufacturers can skip that step, they can begin vaccine production 4-6 weeks earlier than egg-based manufacturers.

Other approaches to accelerating influenza vaccine production involve use of what are referred to as dose-sparing technologies. These are innovations that allow less antigen to be used for each vaccine dose, without compromising immunogenicity or safety. Dose-sparing technologies have the potential to markedly increase vaccine production potential in a pandemic. Adjuvants (compounds that enhance the immune response to a vaccine and therefore reduce the amount of vaccine virus required for each dose) are one such technology. The most commonly used adjuvant today is an aluminum compound found in many childhood vaccines, but which is not used in influenza vaccine. Oil-in-water emulsion adjuvants show the greatest advancement and promise in terms of dose sparing for influenza vaccines. Other potential technologies might involve self-adjuvanting recombinant or molecular vaccines that have built-in antigen-sparing properties.

Other promising candidates and technologies may emerge that lead to development of a universal influenza vaccine, which is the ultimate goal for many influenza vaccine programs. Such a vaccine might need to be given only once, rather than every year as with current seasonal vaccines. Such a universal vaccine would ideally provide protection against all, or at least most, of the many strains of influenza capable of making people sick, including future pandemic influenzas. Plant-produced influenza vaccines are in clinical trials and may prove to be a useful alternative to egg- and cell-based vaccines.


Vaccine Distribution     

In the event of a pandemic, the public and private sectors will mobilize to produce and distribute vaccine, if one is available, as quickly as possible. The CDC’s Advisory Committee on Immunization Practices and other governmental and advisory groups will issue national guidelines prioritizing who should be vaccinated. State and local health departments will develop local modifications to the recommendations as needed. These public health departments will need to make decisions about how to distribute vaccine to providers within their jurisdictions equitably and efficiently with the goal of reaching the priority groups first.

Methods for distributing vaccine in a pandemic are outlined in the , which details public sector pandemic response. The plans are designed to provide guidance to public health coordinators, but also to be flexible enough to adapt to the unique conditions of particular pandemic situation. For example, prior to the 2009 H1N1 pandemic, the most recent pandemic influenza emergency response plans had been based on H5N1 influenza (“bird flu”), which makes sufferers very ill and has a high fatality rate. Planners accordingly projected that health care provider offices would be overwhelmed with caring for the sick and would not have the capacity to administer vaccine. Distribution plans primarily relied on public entities, such as public health departments and hospitals, to receive vaccine and vaccinate most of the targeted population. But because 2009 H1N1 influenza didn’t cause such severe disease, public health authorities realized early on that providers would have the capacity to vaccinate patients. And so vaccine was, for the most part, shipped directly to providers based on the distribution system for the federal Vaccines for Children (VFC) program. This required a few changes to usual VFC procedures, most notably that non-VFC providers, such as retail pharmacies, corporations with occupational health clinics, and non-pediatric health care providers, received and administered vaccines.

Most aspects of vaccine distribution were executed smoothly in the 2009 H1N1 pandemic, especially considering that limited supplies of vaccines had to be allocated fairly and that initial demand was high. The role of certain private vaccine providers attracted media attention and raised some public concern, especially when a few large high-profile private employers received vaccine before some public entities did. No wrongdoing was alleged, but the situation drew attention to the mechanism of vaccine distribution when a variety of public and private provider types are included. However, public health authorities support the use of private occupational health clinics to vaccinate in a pandemic, since they are able to identify and reach many people in high-priority groups.

Reports by state health departments after the pandemic assessing the H1N1 vaccination program suggest a few areas of improvement in a future pandemic: two issues that surfaced frequently in the reports were the need for accurate supply forecasts to inform vaccine ordering and subsequent distribution, as well as the need for clear communication about priority groups for vaccination. For more information, see, for example, the , a , and an .

In addition to challenges with vaccine availability, other potential difficulties may arise in a future pandemic, especially if the illness is severe. The security of the vaccine supply, cold chain requirements, and transport and storage needs may become compromised in emergency situations. The U.S. federal government conducts periodic simulations of biologic emergencies to assess the effectiveness of the public health response and to identify areas where response needs to be improved.


U.S. Concerns, European Concerns, and Developing Countries

The European Union currently has a tool to respond to pandemic influenza threats that the United States has not yet employed. Oil-in-water adjuvants have been used in influenza vaccine in the European Union since 1997, and have an established safety record. But, while plans were made to use adjuvant in the U.S. 2009 H1N1 vaccine, authorities abandoned those and instead approved only unadjuvanted vaccines. Even if adjuvanted influenza vaccine were released, the U.S. public might be reluctant to take the unfamiliar vaccine, in spite of its safety record in the EU.

Vaccine acquisition, distribution, and uptake issues are substantially different in the developing world. Less wealthy countries typically do not widely use influenza vaccine for a variety of reasons, perhaps the most prominent of which is the need to devote health funds to more pressing concerns. In the event of a deadly influenza pandemic or other disease outbreak requiring mass vaccination, governments of developing countries will face significant challenges such as meeting supply needs, funding vaccine acquisition, and ensuring uptake of vaccine in places where influenza vaccination is not commonly practiced.

Under the guidance of the World Health Organization and with the support of various governments, many middle income and developing countries (Brazil, Egypt, India, Indonesia, Iran, Mexico, Republic of Korea, Romania, Serbia, Thailand, and Viet Nam) have established influenza vaccine manufacturing capacity, or are making progress to develop this capacity. The U.S. and Japanese governments have funded influenza vaccine manufacturing capacity in several countries in Latin America and Asia in an attempt to build readiness in the event of an influenza pandemic. Efforts will help to establish seasonal influenza vaccine production that could then be harnessed in an influenza pandemic. WHO officials note that global seasonal influenza capacity has increased from 350 million doses in 2006 to more than 800 million doses in 2011. Because the seasonal vaccine is trivalent (that is, it includes three strains of influenza virus), pandemic vaccine capacity should be roughly triple that of seasonal influenza capacity---2.4 billion doses. This is still far short of total global need, but it is evident that global influenza vaccine production capacity is increasing.



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