Biologic Vaccines

Abstract

The threat of new disease pandemics has spurred the development of biologic vaccines, which promise tremendous improvements in global and local health. Several lend themselves to the prevention or treatment of chronic diseases. But the uncertainties of whom to vaccinate raise the question of whether the health care system can make these promising products viable.

“The paradigm for developing vaccines is changing,” says Steven G. Reed, PhD, at IDRI. “Vaccines for infectious diseases are getting proven in countries where there is a lot of disease, independent of the U.S. market, and we can take advantage of that experience.”

When Survivors — a BBC drama series that posited the outbreak of a lethal virus that quickly kills 90 percent of the world’s population — aired a few months ago, fears mounted about the possibility of such a virus circulating the globe.

Pop culture frequently plays on our basic fears, and dying from an infectious disease is one of them. A spate of recent movies and TV shows —Jeremiah, a U.S. TV series about a postapocalyptic world after an unknown virus kills the adult population, and 28 Days Later, a film about a deadly virus that escapes from a research laboratory, to name just two —have picked up on the increasing emergence of infectious diseases and public concern about them.

The reality is that throughout the world, although not in the United States — yet — infectious diseases can indeed kill off 90 percent of the population. Look at malaria, Ebola, and cholera in Africa.

Germs Go Global: Why Emerging Diseases Are a Threat to America, published by the Trust for America’s Health,1 says that at least 170,000 Americans die annually from newly emerging and re-emerging infectious diseases, and that this number will rise.

The easy movement of people and goods in and out the United States, effects of climate change, and increased drug resistance have all been cited as contributing factors. And then there’s the threat of bioterrorism using smallpox, anthrax, or some other quick-spreading disease as a weapon.

Now, add to this mix, the new biologic vaccines in development. These products upend the definitions of infectious disease, vaccine, and immunization. This may be one of the biggest challenges healthcare providers and payers will face during the 2010s.

TODAY’S CHALLENGES

Once considered chronic illnesses, Kaposi’s sarcoma, Helicobacter pylori ulcers, and cervical cancer, among others, now are thought of as infectious diseases — and the trend seems to be to reclassify even more chronic diseases as infectious. Vaccines now are either prophylactic or therapeutic. And regardless of whether a vaccine can really be called therapeutic — a subject of much contention among disease researchers —those terms are increasingly used to differentiate between, say, a flu shot and a cancer therapy.

Which brings us to Gardasil, a human papillomavirus (HPV) quadrivalent recombinant vaccine developed by Merck, and the first biologic vaccine targeted to a healthy population —girls and young women — to prevent cervical cancer.

Why is Gardasil so important? Because this vaccine is forcing payers, employers, and the medical world to begin thinking about infectious diseases differently, and to confront the many issues that biologic vaccines and mass immunization present.

“When you look at the … health-care system and how people use the system, where do these vaccines fit in? It’s a mess, and it’s a mess for several reasons,” says Fred Ledley, MD, a pediatrician and professor of natural and applied sciences at Bentley University, in Massachusetts.

First, says Ledley, there are fewer primary care physicians — the ones who traditionally give vaccinations. Second, a primary care physician spends, on average, 12 minutes on a wellness visit, and “Describing to the parent of a young teenager why giving an HPV vaccine is smart isn’t a 20-second discussion.” The leading cause of death in children, he notes, is no longer infectious disease but accidents, homicides, and, when you get to teenagers, suicide. “So when the American Academy of Pediatrics says a physician should interview the parent to detect, say, abuse, the physician is going to spend several of those 12 minutes looking for things most likely to cause harm to the child in today’s world. That leaves less time to discuss a threat like cervical cancer.”

Third, Ledley adds, primary care physicians aren’t trained to understand the new biologic vaccines, nor do they have the background to do the kind of counseling mandated by law or ethical practice. “Can a PC or a pediatrician fully explain the risk of cervical cancer?” he asks.

Stephen Lash, PharmD, Genentech’s pharmacy director for value-based healthcare,2 raises another issue: How can mass vaccination for a number of infectious diseases be implemented in a resource- challenged healthcare system? And is that an answer to preventing them?

“How in the world do you know to whom to give biologic prophylaxis?” he asks. “It will take expert people and sophisticated population models to decide who gets a vaccine — and I think in the managed care world this will be a very interesting debate —because you have to decide who is at risk.” In an acute care setting, it’s challenging enough to vaccinate all those at risk for a staph infection —if you can identify them. So identifying who should be protected against more esoteric, but no less dangerous, infectious diseases, such as West Nile virus and Ebola, could be nothing less than an extraordinary task, says Lash.

Albert Tzeel, MD, market medical officer for Humana’s Great Lakes Region, agrees. “What’s good for the individual is not necessarily good for the group and vice versa. But what’s good for the group is to immunize everyone. So, yes, we are going to run into some problems with that.”

Humana has been thinking about infectious diseases for some time. It has an Infectious Disease Clinical Conditions Center Team that looks at everything from benefit design to questions about risk. Gardasil has presented some coverage challenges.

“We had no problem covering girls between the ages of 9 and 18 — they are considered pediatric patients, and Gardasil is a prophylactic vaccine,” says Tzeel. “But for women who are 19 to 26 [included in Gardasil’s FDA indication], we had to change our certificates to cover them.”

Getting people to go along with recommendations presents another, albeit ongoing, challenge. Vaccinations traditionally have had a way of spawning objections based on misconceptions, cultural issues, or moral concerns. The history of vaccinations in this country is riddled with claims that they cause the very disease they seek to prevent or cause other illnesses. Look at the debate over common childhood vaccines and autism, a tempest that refuses to go away despite a lack of conclusive evidence to link the two.

Ledley admits that some physicians find themselves in the middle of a “morality situation” with patients and their parents, especially with a vaccine such as Gardasil. The more time a doctor can spend answering their questions, the better, but still, “The physician only has 12 minutes.”

Perhaps all of these challenges, though, are academic until science sorts out the most elementary one: What should we expect a biologic vaccine against infectious disease to do? When you vaccinate a patient for cervical cancer or for some other chronic disease, “Do you still take precautions to avoid the occurrence of that disease?” asks Lash. “Or do you simply vaccinate and then stop worrying about it?”

COMBINING VACCINATIONS

Today, vaccines are considered prophylactic because they are given to healthy people to prevent a disease — diphtheria, influenza, polio, and malaria, to name a few. But many, if not most, of the new biologic vaccines being developed are considered therapeutic because they are given after a person has contracted an infection, such as HIV, or has a chronic disease, such as certain cancers.

That raises questions about how and when these vaccines should be given. Would a preventive vaccine for an infectious disease be used with a therapeutic vaccine to treat the same infectious disease — and if so, how?

“A beautiful question,” replies Steven G. Reed, PhD, founder and head of research and development at the Infectious Disease Research Institute (IDRI), in Seattle. “In our leishmaniasis [a parasitic disease] and animal models for tuberculosis, the drugs and vaccines work together very well.”

Vaccination Timeline

IDRI is a not-for-profit research institute that develops vaccines, therapeutics, and diagnostics for such diseases of poverty as leprosy, leishmaniasis, and malaria. Its biggest program, though, develops vaccines for both the prevention and treatment of multiresistant (MDR) and extensive drug resistant (XDR) tuberculosis.

Depending on which of those vaccines moves forward first, it would affect the clinical development pathway, says Reed. “We envision two scenarios: After verifying safety, you can go to a high-risk population that will have a good chance of developing active disease within five years, and apply the prophylactic vaccine to see if you can intervene and decrease the number of new cases. Or you can use a therapeutic vaccine in conjunction with drugs to shorten chemotherapy, because the strain may be resistant to the drug alone.” In studies of the drug-resistant leishmaniasis parasite in Latin America, IDRI has found that even though the parasite may be resistant to the drug alone, when a vaccine is combined with chemotherapy, the disease can be successfully treated.

With TB, says Reed, prophylaxis will involve an initial shot and several booster shots. “There are no prophylactic vaccines for TB that are single shot,” says Reed. “We believe that BCG, the current TB vaccine, offers partial protection, and that instead of replacing BCG, we should boost it.

IDRI collaborated with Corixa and GlaxoSmithKline to develop the first recombinant protein TB vaccine effective against all resistant strains of TB. That product is licensed to GSK and is in phase 2 clinical evaluation.

“The impact of vaccines on personal health has been truly amazing,” says Fred Ledley, MD, at Bentley University. “Childhood diseases that were once common are not part of our disease spectrum anymore.”

To Lash, the compatibility of prophylactic and therapeutic vaccines is “the question of the decade, or for coming decades.”

No one yet knows if they are synergistic, he says. Biologics are targeted therapies that adhere to a certain marker on a cancer cell or, in the case of a drug like bevacizumab (Avastin), target the growth factor that supports tumor vasculature. Traditional chemotherapy requires actively growing cancer cells to work, but the newer targeted therapies might not — “and potentially, that’s an enormous conflict.”

Some agents, Lash says, could be nonsynergistic or could impede one another. Moreover, he says, “With slow-growing cancers, an appropriately designed clinical trial could take years, and you would have so many variables you wouldn’t know what to look for unless you are certain that the vaccine on its own is safe and effective.”

Infectious disease: The greatest unmet need

The three deadliest events in human history were caused by infectious disease:

• Bubonic Plague or Black Death (1300s, 1400s, and 1700s): 100 million deaths

• Spanish influenza (1918–1919): 50–100 million deaths

• AIDS (1981–present): 25–30 million deaths and counting. In the United States, of about 1 million cases, 550,000 people had died through 2005. Annual incidence is 23 persons per 100,000.

By the numbers:

• 57,000,000: The number of people worldwide who die annually from infectious diseases.

• 2,700,000: Number of people worldwide who die from malaria each year.

• 2,800: Number of children worldwide who die from malaria each day.

• 36,000: Number of Americans who die each year from influenza and complications.

• 25 percent: Share of physician visits in the United States due to infectious disease complications.

Source: Biotechnology Healthcare analysis

The pathology of much human disease is still not well understood, and pharmaceutical developers generally focus on the molecules rather than disease pathology. “From the biotech view, you are focusing on the receptor and the biologic system,” says Lash. “That’s your starting point. That’s a very different focus.” It raises the question of how many vaccinations can the human body accept —a question that can’t yet be answered.

As such, he offers, third-party payers have to be ready to redefine their concept of the word vaccine and to determine appropriate populations for vaccines. “For health plans, this is going to be an exciting area. They need to become more expert on what’s coming and … how they are going to segment the populations.”

PREVENTION AND WELLNESS

The notion of preventing infectious disease spread parallels the goal of promoting wellness and chronic disease prevention. Problem is, says Ledley, people don’t go to the doctor for wellness care. “Healthy people, once they get through the years of pediatric visits — when you have to get a signature to get into school — don’t go to the doctor. And that applies to the working population as well.”

A vaccination has to show that it makes a difference. The target for any such product that falls under preventive personalized medicine should be adolescents, young adults, and other healthy groups — the same people who do not visit their primary care physicians regularly.

Nor does Ledley think healthcare providers and payers necessarily want to go there, because preventive personalized medicine can become a logistical nightmare and a very expensive proposition without clear guidelines for its use. “There are not enough exam rooms in the system. Even if you have a great product like a vaccine that every 23-year-old should have, you can’t do it.”

Ledley also reminds us of the old managed care saw — that people generally keep their health insurance for about two to three years before moving on to another payer, which removes any incentive for a payer to spend $200 or $300 for a series of vaccinations and another $200 for the physician visits. That, says Ledley, is “an enormous problem for all preventive and predictive medicine.”

Well, yes, says Tzeel, at Humana, but vaccinations such as Gardasil that are recommended by professional societies can be viewed as evidence-based medicine that benefits society and, over time, all payers. “Everybody does this together. You’re right — I may not see that 5-year old after kindergarten, but I may be see that person again at some point.”

To Tzeel — a self-described fan of wellness programs — the challenge in promoting wellness lies in getting information out to those who are candidates for a particular vaccine and to let them know how it will benefit them. And, he thinks, it’s well worth the effort.

SELECTED INFECTIOUS DISEASE EPIDEMICS IN THE UNITED STATES SINCE 1977
Infectious diseases are now classified as newly emerging (N), re-emerging (R), or deliberately emerging (D).
Disease (cause)	Area(s) most affected	Classification (N,R,D)
Anthrax (bacterial)	New York City, N.J., Fla., Conn., D.C.	D (bioterrorism)
Aureus (bacterial)	Mich., PA., N.Y.	R
Dengue fever (virus/mosquito-borne)	Fla., Texas	R
Escherichia coli 0157:H7 (bacteria/food-borne)	Ore., Mich.	N
Hantavirus pulmonary syndrome (HPS) (also known as Sin Nombre virus) (rodent exposure)	Western United States	N
Hepatitis C (virus/contaminated blood)	Southern United States	N
Lyme disease (bacteria/tick-borne)	Northeastern United States	N
Monkeypox (rodents, prairie dogs)	South Central United States	R (first U.S. outbreak 2003)
Parasitic diseases (cyclosporiasis, cryptosporidiosis)	Nationally	R
Tuberculosis (MDR, XDR) (bacterial)	Northeast United States	R
Vancomycin-resistant staphylococcus	North Central United States	N
West Nile virus (mosquito-borne)	Northeast United States	R

MDR=multidrug resistant, XDR=extensive drug resistant.

Sources: CDC 2008, Morens Lancet Infect Dis. 2008

“If we cover a college student for Gardasil or an adult for pertussis, we are not necessarily seeing an immediate positive impact. But like the theory of the commons — where everyone is taking care of the commons instead of overseeing the commons — everyone will get a benefit from it.”3

How or who to vaccinate aside, Ledley agrees with Tzeel on the value of the effort. From a public health and healthcare point of view, he says, prevention is on target. “From the big picture of burgeoning healthcare costs and an aging population, prevention is well worth the investment. It behooves society to do everything to prevent disease rather than to wait.”

NEW BUSINESS MODEL

Yes, but can the U.S. healthcare system afford it? Can the world? Vaccines that wiped out the scourges of the last century proved to be some of the most cost-effective health interventions ever. But new vaccines in development to combat the scourges of the 21st century are likely to cost hundreds, if not thousands, of dollars per person.

As biologics go, Gardasil is “small potatoes — a couple of hundred bucks,” says Thomas Baker, MPA, a principal at IMS Consulting, in Redwood City, Calif. But against other vaccines, he says, the cost would appear to be through the roof. And in mass vaccinations of a large healthy population to prevent an infectious disease, it’s the number of people who need it — not the unit cost — that’s going to drive the cost to society.

That raises a substantial question about cost benefit, and in the United States, he says, “We are not set up to make that kind of evaluation on a population basis.”

SELECTED INFECTIOUS DISEASE VACCINES IN DEVELOPMENT OR CLINICAL TRIALS
Company	Indication
Acambis/sanofi pasteur	Clostridium infections, dengue fever, Japanese encephalitis
Aeras Global/GSK	Tuberculosis
AlphaVax	Cytomegalovirus (CMV) (herpes) infections
Avant Immunotherapeutics	Cholera, typhoid fever
Barr Pharmaceuticals/Teva Pharmaceutical	Oral vaccine in FDA review for adenovirus types 4, 7 for common cold, pneumonia, bronchitis
BioSante	Anthrax, malaria
Biogen Idec	Human papillomavirus (HPV) infections
DynPort Vaccine	Botulism, Yersinia infections
GenePhar	Ebola virus, hepatitis B
GenVec	Coronavirus (SARS) infections, malaria
Genzyme/Advinus Therapeutics	Malaria
GSK	Dengue fever, DPT for adults, herpes, hepatitis E, malaria, meningitis, otitis media, pneumococcal infections, shingles
IDRI	Leishmaniasis
Integrated BioTherapeutics/NIAID	Ebola and Marburg viruses
MedImmune	Epstein-Barr virus, respiratory syncytial virus (RSV)
Merck	Shingles, hepatitis B, HPV, influenza, staphylococcal infections
Novartis/Intercell	Hepatitis A, Japanese encephalitis, pseudomonal infections
sanofi pasteur	CMV (herpes) infections, hepatitis B/polio/influenza combo, meningitis, meningococcal infections, rabies, tuberculosis, West Nile virus
SRI International/NIAID	TB, SARS, avian flu, West Nile virus, hepatitis
Vical	Ebola virus, West Nile virus
Wyeth	Pneumococcal infections in the elderly, RSV
Xanodyne Pharmaceutical	Urinary tract infections

Eighteen vaccines for prevention and/or treatment of HIV infection and 30 vaccines for prevention and/or treatment of influenza (all types) are in clinical trials.

Source: Biotechnology Healthcare analysis

Demand for effective medicines is rising, but so is the disease burden —and not just in underdeveloped countries, says Steve Arlington, PhD, the U.K.-based global leader of Price-waterhouseCoopers’ Pharmaceutical Industry Group. “With the constantly escalating cost of healthcare, we have to ask how healthcare programs will be implemented and sustained.”

By 2020, the global pharmaceutical market will more than double to $1.3 trillion, according to PWC’s report, “Pharma 2020: The Vision –Which Path Will You Take?” A number of factors will contribute to this:

• Costly targeted therapies will continue to emerge and demand for them will grow.

• The population is growing and living longer, some with chronic diseases once thought to be a death sentence. The need is growing for medications, like those for diabetes control, that keep this population healthy.

• Infectious disease incidence is on the rise. Today’s R&D pipeline includes a vaccines sector that has at least 245 pure vaccines and 11 combination vaccines in clinical development. Vaccines for HIV, influenza, hepatitis, malaria, TB, West Nile virus, herpes, anthrax, and severe acute respiratory syndrome (SARS) are garnering most of the R&D dollars.

“If you are going to move toward prevention of infectious and other diseases, then you are going to have to alter the business model,” says Steve Arlington, PhD, of PricewaterhouseCoopers.

Together, these factors will run up a tab that cannot be paid by any one country or healthcare financing system, Arlington argues. Moreover, in its present form, the biotech and pharmaceutical industries are unable to produce innovative treatments — like biologic vaccines — quickly and economically enough to meet infectious disease threats. The answer, he says, has to be greater emphasis on prevention as a part of a new model for meeting the world’s healthcare challenges.

Which brings us back to the question: Prevent what, and whom do you choose to protect?

“Scale is the issue in producing drugs. Scale would temper the cost. Vaccinating 124 million people instead of only 140,000 can make a difference,” not to mention be profitable, Arlington says. “Do the math.”

Prophylactic vaccines have not been profitable, one reason big pharma has, until recently, backed away from large-scale development of vaccines in the last two decades. Making vaccines attractive to manufacturers — at a time when their blockbuster-centered business plan is due for an overhaul — will require some creative thinking.

When pressed as to what would the new business model he urges would look like, Arlington suggests that the pharmaceutical industry may have to get involved in health management, though what form that would take is not clear. Other consultants to the pharmaceutical industry, like Ernst & Young, have suggested that drug makers should consider partnering with health insurance companies to offer “micro” policies in selected emerging markets, such as biologic vaccines, to help patients afford drugs. Whether pharmaceutical companies would want to take on the role of insurer is another question altogether, but some pharma CEOs are giving the idea thought.

ALIGNMENT OF INTERESTS

In the United States, aligning the interests of biopharma companies, government, and the healthcare industry has been touted as a way to meet 21st century healthcare challenges affordably. Like many people, however, Arlington is skeptical that alignment can work without some basic changes in how these entities work in the real world. Each has different agendas and objectives.

Take childhood vaccines, for instance. Combination pediatric vaccines — such as the 5- and 7-valent vaccines — are money losers for pediatricians who struggle with high overhead for vaccines and relatively payment for them. This has led many physicians to resist the use of some combination vaccines, despite the obvious adherence and public health advantages. “We as payers have to address those issues, and we at Humana have begun to do so,” says Tzeel.

Market size and liability: The carrots

One major unresolved issue with the new vaccines is the extent to which the government should shield vaccine developers from liability. Until very recently, U.S. manufacturers have shied away from vaccine development, even with government protection from product liability claims, because profitability was low and most of the big killers, like malaria and Ebola, are not prevalent in this country. Reopening the potential for liability changes the dynamics, at the risk of ignoring unmet needs.

Thomas Baker, MPA, a principal at IMS Consulting, in Redwood City, Calif., has been tracking the vaccine market, and points to Gardasil as an example. “It’s a good product, but we have no idea what the long-term effects will be. To what extent should government bear that risk versus the manufacturer?”

To Baker, it’s not inconceivable that manufacturers should bear some liability for new biologic vaccines. “We have a relatively functional system with vaccines, but if you are talking about something that will have systemic effects that we don’t understand, the level of risk and potential exposure is significant.”

“Hard question to answer,” replies Stephen Lash, PharmD, Genentech’s pharmacy director for value-based healthcare, because not every biologic vaccine will result from a government-championed public health initiative. In fact, he says, it’s unlikely that the government will identify many vaccination needs in the population at large and make their availability a priority. “That hasn’t worked well in the past,” he says, adding that it’s the role of the pharmaceutical or biotech developer to determine if there’s a market.

Yet, if the government offered biologics manufacturers protection from liability, would the R&D investment needed to conquer today’s infectious disease threats be a more attractive proposition?

The markets are there. HIV — now thought to be a mutated anthrax virus — has been around for almost 30 years, yet no effective antiviral therapy has been developed. Unless a cure or treatment is found, the total lethality of the HIV/AIDS pandemic may surpass the 1918–1919 flu pandemic.

An “easy” solution might be mass vaccination programs, more effective public health programs, and disease prevention programs, but these initiatives aren’t easy to implement or sustain.

The possibility of harnessing the immune system so you can vaccinate against HIV or hepatitis, for instance, is compelling, says Baker, and the cost of treating those conditions and the indirect costs of disability or early death are substantial. “So at some point,” he says, “it makes sense to invest in at least the vaccination of at-risk populations.” Citing Gardasil, Baker emphasizes that “It’s one fifth of the population [that can be vaccinated], and every year you have more potential candidates. It’s the size of the target population that counts.”

Whether a manufacturer should be protected from immunity as a lure for meeting unmet needs in these markets is an issue certain to fuel debate.

Tzeel thinks that the new biologic vaccinations may be more expensive, but not outrageously so. And yet, at this point, he concedes, people will not pay for them — at least, not without a clear understanding of the benefit to them — and possibly, a little help shouldering the cost of what some public health advocates may consider a societal responsibility.

In a consumer-directed health plan, he says, the implication “to me as a consumer is that I have to make the decision about being vaccinated because I will pay for it out of pocket. If you charge me $150, it may be valuable to me. If you charge me $150,000, I may put it off.”

Ledley, at Bentley University, is concerned that society may consider alignment to be a conflict of interest. “It’s complicated. I don’t think you want to dictate to the biotech companies what to do. There’s an entrepreneurial energy there that you don’t want to sacrifice.”

But, as many in the medical community have pointed out, prevention is about early diagnosis, not health promotion, and that too costs money.

Arlington gets back to the core issue: Yes, he says, we probably could remove a disease in time, but what are the financial incentives? The biologic vaccines in development are both preventive and palliative. With health-care costs out of control, how —given the way medicines are developed, healthcare is delivered and financed, and with emerging infectious diseases going global — are we going to do it?

It’s a question that is begging for an answer.