Download Alternative Vision. Full Proposal FINAL (A0106742)

An Alternative Vision for the Boston University
National Emerging Infectious Diseases Laboratory
Executive Summary
Marginal value of Boston University’s present focus
There are two major shortcomings of the Boston University (BU) National Emerging
Infectious Diseases Laboratory (NEIDL) plan. First, the proposed research on
bioweapons agents is redundant because there are laboratories throughout the nation
already engaged in this research. Second, the focus on emerging infectious disease has
minimal value compared to research on other kind of infectious disease. The NEIDL
would better serve public health if it conducted research on prevalent natural infectious
diseases and safe technologies rather than its current focus on bioweapons pathogens that
require Biosafety Laboratory Level-4 (BSL4). This paper sets forth such an alternative
vision.
Although Boston University tries to downplay biodefense research, it would be obligated
to carry out biodefense research requested by the National Institutes of Health (NIH).
That obligation flows from the fact that the National Institutes of Health funded the
construction of the NEIDL facility. The focus on biodefense is evident when one
examines the list of organisms that will be studied in the NEIDL. Although BU has been
reluctant to identify the specific pathogens that will be studied despite many requests for
this information, it has recently listed “some of the organisms that will be studied.” Five
of the seven identified pathogens are Category A bioweapons agents. This high
percentage of bioweapons agents contradicts any claim that its focus is emerging
infectious disease. Our Alternative Vision, to the contrary, details a different kind of
research. There would be no need to work on the highly dangerous live BSL4 pathogens
that BU proposes for the NEIDL and no need to divert public health dollars into
biodefense.
We challenge the utility of Boston University’s planned biodefense-related research.
Other laboratories are already researching and developing countermeasures for all the
major bioweapons agents. This focus on BSL4 bioweapons agents is evident in the large
and growing number of bioweapons-related research publications that have appeared
since 2002. We, therefore, question what the BU NEIDL can add at this late stage.
We also question the value of conducting research into so-called emerging infectious
diseases. The term “emerging infectious diseases” has been applied by Boston University
to BSL4 bioweapons agents such as the hemorrhagic fever viruses Ebola, Marburg and
Lassa. The term is misleading as it implies a public health urgency that these pathogens
do not deserve. They, in fact, present no public health threat in the United States and only
a minor health threat anywhere else. Their public health importance pales next to the
pathogens responsible for diarrheal, respiratory, and sexually transmitted disease. In fact,
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the rare BSL4 pathogens should be rightfully classified as “exotic,” not emerging. Only
one pathogen out of seven on BU’s list, Mycobacterium tuberculosis, is a bona fide
public health threat in the U.S. and in most other parts of the world.
In sum, anticipated research on BSL4 pathogens in the Boston University NEIDL has
marginal public health and marginal biodefense value. An alternative focus and costeffective strategy for NEIDL is clearly needed and easily attainable. Such a strategy, we
maintain, should focus on employing and developing new technologies that seek to
prevent and cure infectious diseases of substantial public health concern.
An alternative vision
By refocusing its research on prevalent natural disease and by adopting new, safe vaccine
and antimicrobial technologies, Boston University could make a major contribution to
public health without the hazards of working with dangerous pathogens that require
BSL4 laboratories. With a focus on prevalent natural diseases as opposed to rare and
exotic ones, the possible escape of pathogens from the lab would have less consequence
since those organisms would already be present in the community.
In particular, Boston University should consider countermeasures against prevalent
pathogens such as Staphylococcus aureus, Clostridium difficile, Streptococcus
pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Chlamydia
trachomatis, for which U.S. death rates are high and rising, and for which many strains
are now resistant to most or all antibiotics. These genuinely “reemerging” bacterial
diseases represent a grave public health threat because of growing antibiotic-resistance.
The World Health Organization has identified antibiotic resistance as one of the greatest
threats to human health.
Boston University NEIDL funding could also be more wisely spent on countermeasures
for viruses responsible for respiratory infections, diarrheal diseases, and sexually
transmitted diseases that are major public health threats everywhere, and for those truly
emerging viruses such as West Nile and dengue.
New vaccine technologies employ pathogen mimics that cannot cause infection or
disease. As such, they pose no risk to laboratory workers or to the communities
surrounding the laboratory. Most research and development of vaccines using the new
technologies may be carried out in BSL1 and BSL2 laboratories since special precautions
are not needed.
An even more fundamental criticism of the proposed NEIDL research is that vaccines are
not the best approach for defense against a bioweapons attack. Vaccines require a few
weeks and often several inoculations in order to establish protection. They have some
unavoidable drawbacks such as short shelf life and inability to demonstrate efficacy for
bioweapons vaccines. Vaccines against prevalent diseases generally avoid such
drawbacks as there are ample human subjects to demonstrate efficacy. Moreover, since
the vaccines are in continual use, shelf life is usually not a problem. Vaccines against
bioweapons agents and rare diseases are a “one bug, one drug” approach, as they target
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only one pathogen and sometimes only one strain of a pathogen. Witness the need for
new vaccines each year for the annual flu.
While some of the new vaccine technologies can produce safer vaccines faster than
traditional vaccine manufacture, an emphasis on oral antiviral and antibacterial drugs
would provide a broader and more rapidly deployed defense since they would not require
injections. Broad-spectrum antibiotics and antivirals developed to target prevalent natural
diseases have immediate application to biodefense as well. The broad-spectrum approach
is indeed a way to meet both public health and biodefense needs simultaneously. There is
a pressing need for inexpensive new antivirals and antibiotics which are small-molecule,
broad-spectrum, and orally available to counter natural disease and for biodefense
purposes.
The Boston University NEIDL seems to be hiring staff with expertise on viruses and on
immunology for vaccine development. If, as we have suggested, BU would instead turn
some of its attention to finding new approaches for small-molecule antivirals and
antibiotics, it would then need to bring in expertise to the NEIDL that it may not now
have, in particular in the areas of medicinal chemistry and rapid screening of drug
candidates. A significant medicinal chemistry and screening capability added to the
NEIDL would also serve the Boston-area infectious disease research community, as both
are in short supply. BU should also consider making its Good Laboratory Practice, pilot
manufacturing, and clinical trial expertise available to academic labs and small
biotechnology companies that are currently developing new infectious-disease drugs.
If Boston University does remain focused on biodefense vaccines
If Boston University redirected its efforts towards devising rapid vaccine development
platforms and manufacturing methodologies for seasonal and pandemic influenza, it
would assure the relevance of the NEIDL to both pressing public health needs and to its
required biodefense mission. From this perspective, the National Institutes of Allergy and
Infectious Disease (NIAID) may be amenable to changing NEIDL’s mission away from
“one bug, one drug” goals. Given NIAID’s own refocus on broad-spectrum approaches, it
might be willing to turn the NEIDL toward similar broad-spectrum countermeasures and
vaccine-platform development.
Efficacy demonstration for vaccines against prevalent pathogens would eventually
require clinical trials in humans. In this regard, BU already has plans to carry vaccines
and other countermeasures through phase I safety clinical trials and thus will have in
place the Good Laboratory Practice and small-scale manufacturing necessary for FDA
approval. NEIDL might consider extending this expertise to managing Phase II and Phase
III clinical trials. This would provide a much needed service. For promising new
vaccines or drugs, special consideration should be given to allowing residents of the
surrounding communities to participate in clinical trials.
The full report, which follows, provides documentation for the ideas and assertions made
in this summary.
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An Alternative Vision for the Boston University
National Emerging Infectious Diseases Laboratory
Protecting public health
We are proposing an alternative vision for the National Emerging Infectious Diseases
Laboratory that will be operated by Boston University. Our alternative vision involves
much less risk and much more benefit to the public than the current research plan. Since
our vision does not involve research on any of the live Biosafety level 4 (BSL4)
pathogens slated for use in this laboratory, we would not require this highest level of
containment.
In short, there are alternative strategies for the Boston University (BU) National
Emerging Infectious Diseases Laboratory (NEIDL) facility. Those strategies would better
serve the most pressing public health efforts against natural infectious disease. To the
extent that Boston University has made its intentions known, its research plan for the
NEIDL will not serve the public health needs of either Boston or the nation as a whole.
To the contrary, the alternative strategies discussed here would serve both Boston
University’s emerging infectious disease and biodefense purposes. This report suggests
replacing NEIDL’s current focus with a much safer way to add value to public health
dollars. This alternative strategy emphasizes the safety of our neighboring communities.
There are a number of hazardous activities that are extremely worrisome if housed or
researched in the city of Boston, regardless of the level of biocontainment:

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
Highly contagious pathogens absent or near absent from the natural world (such
as virulent forms of the 1918 pandemic influenza virus and SARS)
Deadly pathogens not endemic to the United States for which there is no cure or
prevention (such as virulent forms of Ebola, Marburg and Lassa viruses)
Weaponized forms of virulent biological weapons agents (such as aerosolized
forms of Bacillus anthracis)
Aerosol studies on virulent pathogen strains (since aerosols are an efficient means
of infecting many people at one time)
The risk of loss of containment of deadly microbial agents that are released either by
accident or by malicious design is multiplied substantially in a crowded urban
environment where many more people can be exposed to and spread disease.
Concerns over NEIDL’s current focus
The current research focus of the NEIDL is emerging infectious disease and biodefense.
While BU tries to downplay its biodefense research plans, it is in fact obligated to carry
out biodefense research at the bidding of NIH. This obligation is memorialized in a
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commitment letter dated January 28, 2003, which states that “the [NEIDL] facility would
be devoted exclusively to biodefense research and other NIAID-defined research
programs for 20 years.” A copy of this commitment letter is provided in Appendix I.
Historically, BU has been less than transparent regarding the pathogens that will be
studied in its NEIDL facility. Recently, however, the NEIDL website recently identified
“some of the organisms that will be studied.”1 A summary of reported fatalities and the
geographic distribution for the identified organisms are presented in Table 1.
Average Yearly Fatalities
Pathogen
Time Period
Worldwide
US
Range
Kyasanur Forest Disease
from 1957
20
0
Limited to Karnataka State, India
Ebola
1976-2008
44
0
Limited to 4 African countries
Marburg
1967-2008
9
0
Uganda
Lassa
***
5,000 to perhaps 50,000
0
Limited to 4 West African countries
Francisella tularensis
(tularemia, rarely fatal)
***
***
~0
Yersinia pestis
(plague)
***
less than 1,000 to 3,000
2
Worldwide
Worldwide. US cases mostly in
the South West
MDR Mycobacterium
tuberculosis 1
2006
1,322,000
644
Worldwide
1.The BU NEIDL will develop vaccines and countermeasures for multi-resistant Mycobacterium tuberculosis . Data reported here
are for all TB cases, not just drug resistant.
Table 1. Some pathogens BU claims that it will study to develop vaccines and other
countermeasures
MDR stands for multiple drug resistant. The table was compiled from data on the CDC’s Special Pathogens
web site (http://www.cdc.gov/ncidod/dvrd/spb/index.htm) and other sources. See Appendix II for specific
references.
Lacking a complete list of pathogens identified for study at the NEIDL, we assume that
the Table 1 list is representative. Of the seven listed agents that BU is planning to study,
five represent almost all the Category A bioweapons agents2. The five Category A agents
are listed below with diseases in parentheses.


Ebola virus (viral hemorrhagic fever)
Marburg virus (viral hemorrhagic fever)
1
The pathogens were listed and identified as targets for study on the Aerobiology Core
(http://www.bu.edu/dbin/neidl/en/research/researchSingle.php?id=9) and the Biomolecule Production Core
(http://www.bu.edu/dbin/neidl/en/research/researchSingle.php?id=10) sections of the NEIDL website
around January 17, 2010. However, the names and some text, including the quote “some of the organisms
that will be studied,” were deleted from the website by January 24, 2010.
2
For the list of Category A, B, and C bioweapons agents and toxins see “Bioterrorism Agents/Diseases,”
Centers for Disease Control and Prevention http://www.bt.cdc.gov/agent/agentlist-category.asp
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Lassa virus (viral hemorrhagic fever)
Francisella tularensis (tularemia, rabbit fever)
Yersinia pestis (plague)
In BU’s 2003 grant application to NIH requesting funding for the NEIDL (BAA-NIHNIAID-NCRR-DMID-03-36 these same bioweapons agents made up 19 of the 24 planned
research projects that BU proposes to conduct in its lab. The remaining 6 projects would
focus broadly on category A/B pathogens (which also include the 5 bioweapons listed
above) and botulinum toxin, yet another category A bioweapon.
Therefore, all of BU's proposed research programs would focus on bioweapons agents.
This contradicts BU’s claim that its focus is emerging infectious disease, not bioweapons
agents.
Indeed, the term “emerging infectious diseases” is misleading as it implies an importance
that these pathogens do not deserve. All of these pathogens have been known for many
years. None causes more than a few deaths in the United States in any year. Except for
Mycobacterium tuberculosis, the small worldwide disease fatalities caused by the Table 1
pathogens and toxins compared to other diseases, and the fact that fatalities and
geographic distribution are not increasing over time (see Appendix II), indicate that they
should be classified as rare or exotic diseases, not emerging ones.
Compare their fatalities to the world-wide death toll from AIDS (over 2 million),
respiratory infections (over 4 million), diarrheal diseases (over 2 million), and sexually
transmitted diseases excluding AIDS (128,000)3, all of which are serious public health
problems in the United States as well as worldwide. There is concern that some of these
diseases--for example, Lassa fever--are significantly underreported in Africa.4 Lassa does
not represent a public health threat in the United States. The fact that it is underreported
does not qualify it as an emerging disease. In any event, live Lassa virus should not be
housed or researched in the BU NEIDL. As befitting its danger, it would require BSL4
containment.
What about defense against bioterrorism?
“To put this in perspective, since 2000 bioterrorism has killed 5 Americans. In the same
time period, influenza-related deaths alone have likely exceeded 300,000 based on CDC
estimates, and other natural infectious diseases have killed hundreds of thousands more.
Annual US morbidity & mortality figures from AIDS (14,000 deaths), opportunistic
infections such as MRSA (19,000 deaths/year) and C. difficile (350,000 infections and up
to 20,000 deaths) speak to unmet and pressing public health need. Consequently the
threat of bioterrorism, which does exist but which is almost certainly minor, needs to be
3
Table A5 in The Global Burden of Disease: 2004 Update, World Health Organization, 2008.
http://www.who.int/healthinfo/global_burden_disease/2004_report_update/en/index.html
4
See for example, Pardis Sabeti’s laboratory website http://www.sabetilab.org/associations.php. Also, in a
personal communication with Lynn Klotz she wrote “Based on new work in Nigeria, the Minister of Health
is revising it's estimated number of Lassa cases from a few thousand each year to hundreds of thousands of
cases and 50,000 deaths. Similarly work is beginning to show that ebola may be widespread in Gabon.”
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seen as only one element in the wider and larger public health war on infectious
diseases.”5
Furthermore, the current plan for the NEIDL would require the use of viral genomes on
plasmid vectors.6 While a few genes for proteins of interest on plasmids for
countermeasure development are necessary, we question the wisdom of propagating viral
genomes engineered into plasmid vectors. This would make category A pathogens easily
portable. Unregulated expansion of this capability will further democratize bioweapons
capability, decreasing biosecurity.
For comparison with Table 1, yearly fatalities caused by some bacterial pathogens and
seasonal flu that are major public health threats are presented in Table 2. The data in
these tables were gathered by the CDC several years ago, and fatalities for the bacterial
pathogens are increasing due to increasing resistance to antibiotics. For instance, the
number of fatalities from Staphylococcus aureus in 2007 was thought to be about
19,000.7 The World Health Organization has identified antibiotic resistance as one of the
greatest threats to human health. 8
Time Period
CDC Estimates of
Average U.S. Yearly Fatalities
Staphylococcus aureus (total)
1999-2005
10,800
Staphylococcus aureus (MRSA-releatd)
1999-2005
5,500
Clostridium difficile
1999-2004
3,440
Streptococcus pneumoniae
(pneumococcal disease) 1
1997
40,000
Seasonal influenza
1990s
36,000
Pathogen
http://www.cdc.gov/EID/content/13/12/1840-G3.htm
http://www.cdc.gov/eid/content/13/9/1417.htm
http://www.cdc.gov/ncidod/eid/vol7no1/schuchat.htm
http://www.cdc.gov/mmwr/preview/mmwrhtml/00047135.htm
http://www.cdc.gov/h1n1flu/estimates_2009_h1n1.htm#Death
Table 2. Centers for Disease Control estimates of fatalities caused by pathogens of major
concern from growing antibiotic resistance.
“Biological Threats a Matter of Balance” January 26, 2010. Issued paper from Scientists Working Group
on Biological and Chemical Weapons of the Center for Arms Control and Non Proliferation
(http://armscontrolcenter.org/)
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Boston University Medical Center’s Associate Director of High Containment, Dr. John Tonkiss and the
Boston Public Health Commission have stated they do not have plans to regulate these plasmids.
7
“Staph Fatalities May Exceed AIDS Deaths,” By Lindsey Tanner, The Associated Press,
October 17, 2007
8
“Prospective antibacterial pipeline running dry,” by Talha Burki. The Lancet Infectious Diseases, Volume
9, Issue 11, November 2009, Page 661
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7
The scientific community has very little interest in most of the BU NEIDL Table 1
pathogens except insofar as they are bioweapons agents, an aspect already being
addressed in other laboratories9. Instead, most infectious-disease research interest is
focused on emerging antibiotic-resistant pathogens such as drug resistant staph (MRSA).
One way to gauge whether the scientific community has responded to concern over
bioweapons agents is to look at the numbers of scientific publication citations in Pub
Med, which lists nearly all publications in medicine throughout the world. The numbers
of scientific publications that mention the pathogens planned for the NEIDL over two
time periods, 1992-1999 and 2002-2009 are presented in Table 3.
______________________________________________________________
Number of Publications
Biological Weapons
Agents & Toxins
1992-1999
Biocontainment Level
(BSL2, BSL3, BSL4)
2002-2009
Category A
Ebola virus
Marburg virus
Lassa virus
Bacillus anthracis
Francisella tularensis
Yersinia pestis
268
630
4
291
424
4
58
178
4
335
2,294
2,3
239
823
2,3
520
1,239
2,3
Other agents
Kyasanur forest disease virus
340
508
4
Mycobacterium tuberculosis
8,244
15,829
2,3
Totals:
10,295
Percent increase:
(from 1992-1999 to 2002-2009)
21,925
113%
Eliminating Mycobacterium tuberculosis and KFD virus from the list:
Totals:
1,711
Percent increase:
(from 1992-1999 to 2002-2009)
5,588
227%
____________________________________________________________________
Table 3. Pub Med citations and biosafety level for the BU NEIDL pathogens
The search terms used were the formal names of the pathogens, since these were more likely to generate
lists of actual scientific publications compared to using, for example, the disease names. Pub Med was
accessed between March 13 and 15, 2010.
There is a large increase in publications, 113%, between the time periods 1992 - 1999
and 2002 – 2009 for the NEIDL pathogens. If Mycobacterium tuberculosis and KFD
virus are eliminated from the list, the increase in publications for the Category A
bioweapons agents is a whopping 227%. Thus, the pathogens of concern for biodefense
are being actively researched in many laboratories (see below and footnote 9). BU is late
in the game; therefore, we question what the BU NEIDL can add at this juncture.
The 227% increase in publications is due to the billions of dollars that have been poured
into biodefense since the anthrax letters of 2001. This reinforces the idea that the billions
9
A large number of laboratories are researching and developing countermeasures for the Category A
bioweapons agents. This is easily confirmed by searching PubMed
(http://www.ncbi.nlm.nih.gov/sites/entrez) using the name of any agent as the search term.
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in research funding for biodefense may redirect research away from infectious disease of
public health concern.
All the pathogens requiring BSL4 containment are responsible for only a few fatalities
worldwide compared to major public health threats and almost no fatalities in the United
States (Table 1). The hundreds of millions of dollars to build, maintain, and carry out
research on the BU NEIDL pathogens over the years has little public health or added
biodefense value. An alternative, cost-effective strategy and focus for NEIDL are clearly
needed. Such a strategy, we maintain, should focus on preventatives and cures for natural
infectious diseases of substantial public health concern.
An alternative vision
By adopting new, safe vaccine and antimicrobial technologies and refocusing its research
and development to natural disease, BU can make a major contribution to public health
without the public safety dangers of working with virulent pathogens that require BSL4
laboratories.
A BSL3/BSL4 service facility
For particularly virulent or highly contagious pathogens not prevalent in the U.S., a BSL4
laboratory would only be required for short periods of time, only at the beginning (e.g.
isolation and cloning of genes from recently isolated live pathogens) and end of projects
(e.g. studying the efficacy of drugs and vaccines in challenge experiments in animals).
For the time being, these beginning and end procedures can be carried out in other BSL4
labs already working with these pathogens.
But there is a better way, which is safer for the communities that already house BSL3 and
BSL4 laboratories. A large BSL3/BSL4 service facility should be created whose sole
function is testing countermeasures against live deadly pathogens on behalf of
researchers developing them elsewhere. The facility should be located far from any
population center, in the desert or on an uninhabited coastal island for example. In
addition to the physical barriers, for added insurance those who research highly
contagious pathogens would work in days-long stints and then remain in quarantine for a
short period afterward. This would cover multiple risks that are currently unattended,
such as working on the live 1918 pandemic flu virus that killed 40 million people around
the world and could potentially do it again if accidentally reintroduced. Against the
chance of an outbreak that could kill millions this level of added protection seems to us a
must. Moreover, we could substantially reduce the number of BSL3 labs scattered
throughout cities and eliminate the need for all planned urban-area BSL4 labs.10
The following discussion summarizes some of the new, safe technologies and how they
may be applied to development of vaccines, antivirals and antibiotics. The goal is to
“One Bug, One Drug: Boston University’s March to Irrelevance,” Huffington Post May 2 2010
http://www.huffingtonpost.com/dr-lynn-c-klotz/one-bug-one-drug-boston-u_b_559855.html
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suggest technologies with which safe research and countermeasure development can be
carried out. These new technologies would allow the NEIDL facility to become an
important contributor to solving pressing infectious disease problems and conduct
biodefense countermeasure development (if it must) in a safe and cost-effective way.
New vaccine technologies
In Table 4, several new vaccine technologies are listed along with comments on their
status. The technologies are described in laypersons’ terms with examples and quotations
from the scientific literature in Appendix III. The main point from the Table and
Appendix, which cannot be emphasized enough, is that none of these technologies
require live pathogens, so vaccines using any of them may be developed at low BSL1 or
BSL2 levels.
Some New Vaccine Technologies
Technology
Brief Comments from Selected Experiments
Virus-like particles (VLP)
-- Marketed vaccines for hepatitis B and human papilloma virus employ VLPs.
-- VLPs for Ebola and Marburg viruses show high promise.
Non pathogenic or attenuated
recombinant virus vehicles
-- Monkeys vaccinated with attenuated recombinant vesicular stomatitis virus
carrying a Marburg virus gene were protected against Marburg virus.
-- Monkeys also protected when vaccine administered post exposure.
Toll-like receptor (TLR) agonists
-- TLR-3 agonist coupled with double-stranded RNA can serve as
a broad-spectrum vaccine against a number of flu viruses.
-- Mice immunized with the F1 antigen of Yersinia pestis and flagellin
was protective against virulent Y. pestis with 93 to 100% survival.
Bacterial ghosts (BG)
DNA vaccines
-- Oral vaccine consisting of Edwardsiella tarda ghost
protected 86.7% of infected mice from E. tardia infection.
-- Oral vaccines are superior for biodefense because of
ease of administration.
-- DNA vaccines ideal for quick response to a
newly encountered pathogen in a biodefense setting.
-- DNA vaccines under development for B. anthracis , Ebola, Marburg and
smallpox viruses.
-- Potency is still an issue.
Table 4. Some new vaccine technologies and developments with comments to indicate
their status and promise. References and details in Appendix III.
The complete immunity conferred to mice and non-human primates and the strong
immune response and safety in humans in the studies in Table 4 (detailed in Appendix
III) shows high promise for these new technologies for vaccines against the Category A
biological weapons agents. Except for projects where BU researchers are already
involved, this calls into question the need to develop additional vaccines for these
pathogens. This is especially true of the NEIDL pathogens that require BSL4
containment since those viruses are not a public health threat. Instead, vaccine
development for pathogens that are public health concerns in the U.S. or are growing
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threats would make much more sense as a focus. In those cases, multiple efforts can be
justified.
Efficacy demonstrations for vaccines to prevalent pathogens would eventually require
clinical trials in humans. In this regard, BU already has plans to carry vaccines through
phase I safety clinical trials, so it will have in place the Good Laboratory Practice (GLP)
and small-scale manufacturing necessary for FDA approval of phase I trials. NEIDL
might consider extending its clinical trial expertise to managing phase II and III clinical
trials. The pilot-scale manufacturing for phase II and III clinical trials could be
outsourced or carried out in the planned Biomolecule Production Core. This would
provide a much needed service to countermeasure developers that include research
institutions and biotechnology companies focused on infectious disease.
New thinking at the cutting-edge of vaccine development
Some of the vaccines and technologies in Table 4 incorporate cutting-edge ideas. At a
2007 Keystone Symposium11 where many of the world’s vaccine experts met, the
organizers laid out the challenges.
“Even with the large increase of our understanding of host immune responses, the
sequencing of pathogen genomes, and other technological advances, important hurdles
remain for developing and deploying vaccines for a variety of diseases. The goals of this
meeting will be to bring together scientists, physicians and students from the developed
and developing world to discuss the advances in (1) understanding the generation of
effective systemic and mucosal immunity at a cellular and organ system level, (2) new
technologies for prophylactic and therapeutic immunization, including those useful for
resource-poor settings…”
Research and cutting-edge ideas and technologies discussed at the meeting for present
and future vaccine development include:
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
Mucosal immunity
o understanding mucosal immunity
o development of mucosal vaccines (e.g., oral and nasal-spray vaccines)
o plant-produced oral vaccines
Manipulating the immune system to improve vaccine performance
o transforming innate immunity into adaptive immunity
o toll-like receptors and their agonists
Needle-free vaccine delivery
o inhaled and nasal aerosols utilizing nanoparticles and stable dry powders
o targeting vaccines to the immune system
o delivery via lipids
“Challenges of Global Vaccine Development,” Keystone Symposia Meeting. Organizer(s): Margaret Liu,
Paul-Henri Lambert and Sir Gustav Nossal, Cape Town, South Africa, October 8 - 13, 2007
http://www.keystonesymposia.org/meetings/viewPastMeetings.cfm?MeetingID=905&CFID=2304413&CF
TOKEN=64018981
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o dermal patch delivery
o bacterial spores for heat-stable vaccine delivery
Neonatal and infant immunity and vaccines
Polysaccharide vaccines
Development of mouse models for vaccine testing
Some of the ideas and technologies in the bulleted list are still at the research stage and
may not find use in actual vaccines for years. Nonetheless, they represent the cuttingedge of vaccine development that should be built into BU NEIDL thinking and activities.
Of particular interest is mucosal immunity and vaccines targeted to mucosal membranes.
Unless we have a wound or some other way directly into the blood stream, pathogens
enter the body through the mucous membranes.
The key advantage of vaccines directed to mucosal membranes is that they may be
delivered nasally or orally. In response to a pandemic or bioweapons attack oral and nasal
vaccines can be self-administered in contrast to syringes, needles, doctors or nurses
needed to administer a systemic vaccine.
The problem with biodefense vaccines
Vaccines appear to be a major focus of BU’s NEIDL. But vaccines are not the best
approach for defense against a biological weapons attack. They have some unavoidable
drawbacks. The Scientists Working Group on Biological and Chemical Weapons of the
Center for Arms Control and Non Proliferation’s calls into question the usefulness of
biodefense vaccines.
“[A]gencies and programs have been set up at great expense, with the aim of having
available stocks of vaccines against potential bioweapons agents. Many questions remain
about these programs with respect to vaccine efficacy, safety, shelf life and the ability to
perform mass immunizations at short notice. Until these issues are resolved the
effectiveness of vaccines as countermeasures remains in doubt.
Countermeasures effective after exposure to anthrax and the smallpox virus, the
bioterrorist threat agents of greatest concern, have been developed and stockpiled—
antibiotics for anthrax and a vaccine for smallpox. Efforts to accumulate stockpiles of
more novel therapeutics, or ones targeted to even less likely bioterrorist threats, are not
cost-effective unless they would also serve clear public health goals.”12
Of particular note is that an author of this paper is Jack Melling, who was the Chief
Executive and Principal Scientific Officer at Porton Down, the UK biological weapons
defense facility and U.K. equivalent to USAMRIID in the US. He also directed the Salk
Institute Biologicals Development Center in Pennsylvania and the Karl Landsteiner
Institute for Vaccine Development in Vienna, Austria. Melling is among the world’s
experts on vaccines against biological weapons agents.
12
“Biological Threats a Matter of Balance” op. cit.
12
Vaccines have other drawbacks as well. Traditional vaccines protect against one specific,
targeted pathogen. If that pathogen is, for example, one of those rare pathogens listed in
Table 1, the vaccine will have no public health value in the United States.
The National Institute of Allergy and Infectious Diseases (NIAID) recent update of its
biodefense strategy acknowledges this drawback.
“Although the focus of this updated Strategic Plan continues to be on basic research and
its application to product development, there is a shift from the current “one bug-one
drug” approach toward a more flexible, broad spectrum approach. This approach involves
developing medical countermeasures that are effective against a variety of pathogens and
toxins, developing technologies that can be widely applied to improve classes of
products, and establishing platforms that can reduce the time and cost of creating new
products.”13
Said another way, vaccines against bioweapons agents and rare diseases are a one-way
street. For the most part they have no value for natural diseases prevalent in the U.S. In
contrast, broad-spectrum antivirals and antibiotics developed to target prevalent natural
diseases will have immediate application to biodefense as well. The broad-spectrum
approach is indeed a two-way street, that is a way to meet public health and biodefense
needs simultaneously. This would also ensure taxpayers get greater public health value
for their tax dollars.
Another NIAID suggestion to “[e]stablish manufacturing platforms…for rapid and costeffective production of therapeutics and vaccines for human use. Expand clinical trial
capabilities for evaluation of new drugs”14 should fit well with BU’s NEIDL planned
clinical trials expertise.
Focusing on rapid vaccine development and manufacturing methodologies, targeting for
example seasonal influenza and other prevalent diseases, would help make BU’s NEIDL
particularly relevant to urban community needs. Furthermore, with a focus on diseases
already spread throughout the population, escape of the pathogen from the lab would
have little consequence.
A better focus: broad-spectrum, small-molecule antivirals and
antibiotics
Why small-molecule drugs are far better
Small-molecule antivirals and antibiotics have a number of advantages over biologic
drugs15 and vaccines. A summary comparison is presented in Table 5.
“NIAID Strategic Plan for Biodefense Research – 2007 Update,” National Institute of Allergy and
Infectious Diseases. September 2007 www.niaid.nih.gov
14
Ibid
15
In this document, biologic drugs refer to large-molecule drugs comprised of proteins including
monoclonal antibodies (MAbs), DNA RNA, and other large-molecules found in living organisms.
13
13
Cost
Stability in Storage
Oral Delivery
Safety
Small-Molecule
Antimicrobials
Traditional
Vaccines
New
Vaccines
low
stable
yes
safe
low
unstable
no
may be unsafe
may be expensive
unstable
maybe
safer than traditional
Table 5. Advantages of small-molecule antimicrobials
Insight into cost issues may be gleaned from looking at what the U.S. government pays
for various countermeasures for the Strategic National Stockpile (SNS). Cost data for
countermeasures procured under BioShield 2004 funding16 are summarized in Table 6.
Countermeasure
name
Type of
countermeasure
Anthrax Vaccine Adsorbed (AVA)
(Emergent BioSolutions)
ABthrax
(Human Genome Sciences)
Anthrax Immune Globulin (AIG)1
(Cangene Corporation)
Botulism Antitoxin Heptavalent
(Cangene Corporation)
Number of
Doses
(thousands)
(millions)
Price
Price
per dose
vaccine
10,000
$243
$24
humanized Mab
20
$165
$8,250
passive immunization
10
$144
$14,400
polyclonal antibody
200
$363
$1,815
2
3
IMVAMUNE®
(Bavarian Nordic)
ST-246®
(SIGA Technologies, Inc.)
Pediatric liquid Potassium Iodide
(Fleming & Co.)
smallpox vaccine
80,000
$680
$8.50
smallpox oral antiviral
proteinase inhibitor
1,700
??
??
inorganic compound
1,700
$5.7
$3.35
1. Immuneglobulin derived from plasma obtained from donors immunized with the Anthrax vaccine.
2. Antibodies specific for the seven botulinum toxin types
3. Price includes both development and procurement
Table 6. Number of doses purchased, total cost, and cost per dose for countermeasures
purchased for the Strategic National Stockpile under Bioshield 2004 funding
References for the numbers are:
http://www.hhs.gov/aspr/barda/mcm/medcountmeas.html
http://archive.hhs.gov/news/press/2006pres/20060601.html
http://www.medicalnewstoday.com/articles/21519.php
http://www.bavarian-nordic.com/investor/announcements/2009-27.aspx
http://www.bavarian-nordic.com/investor/announcements/2010-25.aspx
http://www.siga.com/?ID=107
16
The Project BioShield Act of 2004 authorized $5.6 billion to purchase countermeasures for the Strategic
National Stockpile. It was signed into law on July 21, 2004 (P.L. 108-276).
14
On a per dose basis, the most expensive countermeasures are those for the biologic drugs:
the humanized monoclonal antibody for anthrax, the passive immunization with
immunoglobulins for anthrax, and the polyclonal antibodies for botulinum toxin
poisoning. Passive immunization is the most expensive, likely because collecting and
processing immunoglobulins from people who have had anthrax vaccinations is
expensive. High cost also limits the number of doses that can be purchased for the SNS.
Biologic drugs are delivered by injection, which is another drawback in a biodefense and
pandemic setting.
Both the anthrax and smallpox vaccines are inexpensive, as the production methods are
no more complicated than those for many traditional vaccines. The anthrax vaccine is
prepared from a culture filtrate made from a non-virulent strain of Bacillus anthracis and
contains no dead or live bacteria.17 The smallpox vaccine is prepared from a Vaccinia
virus strain that cannot replicate in human cells, solving the main safety problem of older
smallpox vaccines.18
Unfortunately, some vaccines based on new strategies may be expensive if they contain
recombinant proteins made by fermentation. For example, the human papillomavirus
(HPV) vaccine GARDASIL is priced at $120 per single dose, and three doses are
required.19 The vaccine is prepared from recombinant major capsid (L1) protein of four
HPV types using yeast fermentations.20 Some recombinant vaccines may be considerably
more expensive than GARDASIL if they require fermentations of animal cells.
Humanized monoclonal antibody drugs, such as ABthrax, are made by fermentations of
animal cells. They can cost several thousand dollars per gram to make. Smaller
recombinant proteins can cost hundreds of dollars per gram.21 Recombinant biologic
drugs often sell for thousands of dollars per dose.
In contrast, small-molecule drugs can be produced for $1 to $10 per gram, and usually
sell for $1 to $10 a dose, which can be verified simply by visiting any on-line pharmacy.
Small-molecule drugs often can be taken orally. Low price and oral delivery are the
major advantages that small-molecule drugs offer, which is why they have been and will
continue to be the mainstay of the pharmaceutical industry.
The need for new antibiotics and antivirals
17
http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ucm061751.htm
Bavarian Nordic website http://www.bavarian-nordic.com/biodefence/smallpox/imvamune.aspx
19
http://cervicalcancer.about.com/od/riskfactorsandprevention/f/vaccine_cost.htm
20
http://www.merck.com/product/usa/pi_circulars/g/gardasil/gardasil_pi.pdf
21
J McArdle, “Alternatives to Ascites Production of Monoclonal Antibodies” Animal Welfare Information
Center Newsletter, Winter 1997/1998, Vol. 8, no. p3-4. RK Sundaram, et al., “Expression of a functional
single-chain antibody via Corynebacterium pseudodiphtheriticum” Eur J Clin Microbiol Infect Dis. 2008
Jul;27(7):617-22. A Lewcock, “”Down on the biopharm,” 17-May-2007 http://www.inpharmatechnologist.com/Industry-Drivers/Down-on-the-biopharm
18
15
Because of increasing microbial resistance to antibiotics, there is an urgent need for new
broad-spectrum antibiotics. As reported in the prestigious British medical journal The
Lancet
“WHO [World Health Organization] has identified antibiotic resistance as one of the
greatest threats to human health…Yet prospects for replacing current antimicrobial drugs
are poor. Only a single new antibacterial—doripenem—has been approved in the USA
since 2006… [J]ust 15 antibacterial drugs that offer a potential benefit over existing
drugs are in development, and only five have reached phase 3 clinical trials.
Pharmaceutical companies may not perceive development of antimicrobial drugs to be
attractive—owing perhaps to a clinical need restricted to short courses of therapy, and the
likelihood that the drugs' useful lives will be truncated by resistance.”22
Since there are only a few somewhat effective antivirals in our armamentarium, there is a
great need for new broad-spectrum antivirals as well. Only four antiflu drugs are
available today: two older drugs amantadine and rimantadine, and the newer zanamivir
(Relenza) and oseltamivir (Tamiflu). The state of affairs was described in Chemistry and
Engineering News, the magazine of the American Chemical Society.
“Flu virus subtypes are designated by their surface proteins: one of 16 possible
hemagglutinins (H1–H16) and one of nine neuraminidases (N1–N9). Despite the large
number of possible permutations, human flu is generally caused by H1, H2, and H3
subtypes in combination with N1 or N2.
In principle, four antiviral flu drugs are available. But like many seasonal flu viruses and
the H5N1 avian flu strain, novel H1N1 is resistant to amantadine and rimantadine …
Relenza (zanamivir) and Roche’s Tamiflu (oseltamivir), both neuraminidase inhibitors,
are still effective.”23
But Relenza and Tamiflu are not wonder drugs; and like antibiotics, resistance may
develop.
“At best, the available drugs reduce the duration of the illness by a day or so… Viral
resistance could also shorten the drug’s useful life. In the 2007–08 flu season, a Tamifluresistant seasonal H1N1 virus unexpectedly arose naturally in Europe. So far, however,
only about two dozen isolated cases of Tamiflu resistance in the novel H1N1 virus have
appeared… [The manufacturer Roche emphasizes] the drug’s apparent ability to
prevent infection about 90% of the time and to decrease the severity of illness by 40%
and hospitalizations by 61%.”24
New antivirals
“Prospective antibacterial pipeline running dry,” by Talha Burki. The Lancet Infectious Diseases,
Volume 9, Issue 11, November 2009, Page 661,
22
23
24
“Flu Fighters,” by Ann M. Thayer. C&EN, Volume 87, Number 39, September 28, 2009 pp. 15 - 26
Ibid
16
This discussion will focus on new antivirals, not antibiotics, since the BU NEIDL seems
to be focusing and building staff in viruses and immunology, although it might consider
bringing aboard expertise in bacterial pathogens and antibiotics.
Table 7 provides a summary of promising new antivirals along with comments and status.
Details on these new antivirals are found in Appendix V.
Some New Antiviral Drugs
Drug Class
Brief Comments
Neuraminidase inhibitors
(spectrum of activity is limited to flu viruses)
>> Laninamivir is long acting. It has completed Phase III trials in Asia
>> Peramivir as effective as a week’s supply of Tamiflu. It has
completed Phase II clinical trials
Broad spectum antivirals
>> Favipiravir works against flu viruses including H5N1, influenza A,
influenza B, influenza C, poliovirus, rhinovirus, yellow fever virus,
respiratory syncytial virus, arenavirus and West Nile Virus. It is
about to enter Phase III clinical trials for seasonal flu in Japan
>> DAS181, an inhaled viral entry blocker, prevents respiratory viruses
from infecting cells.It is comprised of two co-joined proteins, so may be
very expensive to manufacture
>> LJ001, a broad-spectrum antiviral targeting entry. Effective against
numerous enveloped viruses including Influenza A, filoviruses, poxviruses,
arenaviruses, bunyaviruses, paramyxoviruses, flaviviruses, and HIV-1
RNA interference-based antivirals
>> Small interfering RNA (siRNA) drugs can be readily made to
recognize and destroy messenger RNAs from any invading virus.
mRNA sequences are known for most pathogens
and viral bioweapons agents
Table 7. Some new antivirals in development with comments to indicate their status and
promise.
For years, the knock against antivirals has been that they employ our own cell’s
“machinery” to reproduce, so most strategies for new antivirals would yield drugs that are
not particularly effective or have severe side effects if they didn’t outright kill us. This
concern over antivirals seems to be borne out by the fact that there are only four antivirals
on the market today (excluding HIV drugs), which aren’t particularly effective. But as
virologists learn the molecular details of how virus mechanisms differ from those of the
human host, new strategies for antivirals are becoming apparent. New strategies, as
evidenced by the drugs described in Table 7 (and in more detail in Appendix V), may be
the harbingers of a host of powerful new antivirals.
Now would be the time for the BU NEIDL to consider entering the fray by developing
broad-spectrum antivirals for natural infectious disease that could have biodefense
applications as well.
A small-molecule drug focus for NEIDL
17
Small-molecule, broad-spectrum, orally available, and inexpensive new antivirals and
antibiotics are the most pressing need for both natural disease and biodefense. In order to
refocus on new approaches to small-molecule drugs, NEIDL would need to bring on
expertise that they may not now have, in particular medicinal chemistry and rapid
screening of drug candidate molecules. A significant medicinal chemistry and screening
capability could also serve the Boston area infectious disease research community as
well, as both are in short supply. BU should also consider making its Good Laboratory
Practice, pilot manufacturing and clinical trial expertise available to academic labs and
small biotechnology companies developing new infectious-disease drugs.
Importantly, screening for small-molecule drugs is normally done using in vitro and in
vivo reporter assays which do not require access to the intact pathogen. As described
earlier, a majority of the work can take place without the pathogen, until the final, livechallenge experiments. These proof-of-efficacy experiments can be carried out in BSL3
and BSL4 laboratories that are equipped to work with those pathogens.25 Also, broad
spectrum antimicrobials can be discovered using less pathogenic microbes; and the most
promising drug candidates can then be tested on more pathogenic targets in existing
facilities, or eventually in a service facility as proposed here.
Conclusion
We have grave concerns over NEIDL possessing or experimenting with virulent forms of
pandemic flu viruses such as the 1918 flu virus. Even though the risk of escape may be
small, the consequences could be enormous. Uncomfortable over the resurrection of the
1918 pandemic flu virus by U.S. scientists, Dr. Donald Henderson, who was a leader in
the WHO smallpox eradication campaign, said, "The potential implications of an infected
lab worker – and [of] spread beyond the lab – are terrifying."26
Work with highly contagious, deadly pathogens should be carried out only in facilities far
away from population concentrations, as described earlier. To perform the research set
forth in this "Alternative Vision," it is not necessary to work with any of the dangerous,
live BSL4 pathogens that BU lists for use in its proposed NEIDL. We therefore hope that
this Alternative Vision will be adopted.
25
For a partial list see: http://en.wikipedia.org/wiki/Biosafety_level#List_of_BSL-3_and_BSL-4_facilities.
For a map of major facilities see http://www.fas.org/programs/bio/biosafetylevels.html
26
“Experts fear escape of 1918 flu from lab,” Debora MacKenzie, New Scientist, October 2004
http://www.newscientist.com/article.ns?id=dn6554
18
Appendix I. Letter written by Boston University officials to the National
Institute of Allergy and Infectious Disease
19
Appendix II. Trends in incidence, fatalities and geographic distribution for
the BU NEIDL pathogens listed in Table 1.
For Ebola and Marburg viruses, two of the NEIDL pathogens that BU claims as “some of
the organisms that will be studied,” trend data for fatalities over time and for geographic
distribution are presented below:
Ebola virus
Ebola Outbreaks
Year
Fatalities
Location
1976
1976
1977
1979
1994
1995
1996
1996
1996
2000
2001
2001
2003
2003
2004
2007
2008
280
151
1
22
31
250
26
45
1
224
53
43
128
29
7
87
37
Sudan
Zaire
Sudan
Gabon
Republic of
Gabon
Gabon
Gabon
Uganda
Gabon
Republic of
Republic of
Republic of
Sudan
Republic of
Uganda
Total:
Zaire
Congo (Zaire)
Congo (Zaire)
Congo (Zaire)
Congo (Zaire)
Congo (Zaire)
1415
Years spanned:
Average fatalities per year:
32
44.2
Source: http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/ebola/ebolatable.htm
Marburg virus
Marburg Outbreaks
Year
Fatalities
1967
7
1975
1980
1987
1988-2000
2004-2005
2007
2008
1
1
1
128
227
1
1
Total:
Years spanned:
Avg fatalities per year:
Location
Germany and Yugoslavia via Uganda
Johannesburg, South Africa via Zimbabwe
Kenya
Kenya
Republic of Congo
Angola
Uganda
Netherlands via Uganda
367
41
9.0
Source: http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/marburg/marburgtable.htm
20
For the other pathogens that the BU NEIDL claims it will study, there are either
incidence data over time and geographic distribution or written statements indicating that
the diseases caused by the pathogens are not increasing over time or range is increasing.
These data are presented below.
Lassa virus
Lassa Fever Outbreaks
Year
Suspected
Cases
1999
320
2000
2001
2002
2003
275
260
300
145
Total:
Location
Germany and Yugoslavia via Uganda
Johannesburg, South Africa via Zimbabwe
Kenya
Kenya
Republic of Congo
1300
Note: This data is for a single hospital, the Kenema Government Hospital in Sierra Leone,
but should be representative of overall trends over time for the disease in Western Africa
Source: http://www.who.int/disasters/repo/10497.pdf
The following quote provides incidence and fatalities in West Africa, where Lassa fever
is endemic:
“The number of Lassa virus infections per year in West Africa is estimated at 100,000 to
300,000, with approximately 5,000 deaths. Unfortunately, such estimates are crude,
because surveillance for cases of the disease is not uniformly performed. In some areas of
Sierra Leone and Liberia, it is known that 10%-16% of people admitted to hospitals have
Lassa fever, which indicates the serious impact of the disease on the population of this
region.” http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/lassaf.htm
Kyasanur Forest Disease virus
Kyasanur Forest Disease Outbreaks
There are approximately 400-500 cases of KFD per year with a case fatality rate of 3% to 5%
Cases
Fatality rate
Fatlities per year
450
4.5%
20.25
Source: http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/kyasanur.htm
Note: Data for trends over time not found.
21
Mycobacterium tuberculosis
Among U.S. born persons, incidence of tuberculosis in the U.S. has been decreasing in
recent years. For foreign born persons, incidence has remained constant.
http://www.cdc.gov/mmwr/preview/mmwrhtml/figures/m5910a2f2.gif
“In total, 12,904 TB cases (a rate of 4.2 cases per 100,000 persons) were reported in the
United States in 2008. Both the number of TB cases reported and the case rate
decreased; this represents a 2.9% and 3.8% decline, respectively, compared to 2007. The
TB rate in 2008 was the lowest recorded since national reporting began in 1953… There
were 644 deaths from TB in 2006, the most recent year for which these data are available.
Compared to 1996 data, when 1,202 deaths from TB occurred, this represents a 46%
decrease in TB deaths in the last decade.”
http://www.cdc.gov/tb/publications/factsheets/statistics/TBTrends.htm
Estimated TB incidence, prevalence and mortality, 2008
Incidence1
Prevalence 2
Mortality
WHO region
no. in
thousands
% of global
total
rate per 100 000
pop3
no. in
thousands
rate per 100 000
pop
no. in
thousands
rate per 100 000
pop
Africa
2 828
30%
351
3 809
473
385
48
The Americas
282
3%
31
221
24
29
3
Eastern
Mediterranean
675
7%
115
929
159
115
20
Europe
425
5%
48
322
36
55
6
South-East Asia
3 213
34%
183
3 805
216
477
27
Western Pacific
1 946
21%
109
2 007
112
261
15
Global total
9 369
100%
139
11 093
164
1 322
20
1
Incidence is the number of new cases arising during a defined period.
2
Prevalence is the number of cases (new and previously occuring) that exists at a given point in time.
3
Pop indicates population.
http://www.who.int/mediacentre/factsheets/fs104/en/print.html
Globally, more than 1.3 million persons died of tuberculosis in 2008.
Yersinia pestis
22
Plague causes very few deaths in the United States and is not a major infectious disease
concern in the rest of the world.
“About 14% (1 in 7) of all plague cases in the United States are fatal … Human plague in
the United States has occurred as mostly scattered cases in rural areas (an average of 10
to 20 persons each year). Globally, the World Health Organization reports 1,000 to 3,000
cases of plague every year.”
http://www.cdc.gov/ncidod/dvbid/plague/resources/plagueFactSheet.pdf
Francisella tularensis
Tularemia or rabbit fever, the disease caused by Francisella tularensis, is rarely fatal.
Quoted below are incidence statistics.
“During 1990--2000, a total of 1,368 cases of tularemia were reported to CDC from 44
states, averaging 124 cases (range: 86--193) per year …Four states accounted for 56% of
all reported tularemia cases: Arkansas (315 cases [23%]), Missouri (265 cases [19%]),
South Dakota (96 cases [7%]), and Oklahoma (90 cases [7%]).”
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5109a1.htm
23
Appendix III. Descriptions of new vaccine developments and technologies
Lay-level introduction to vaccines
Vaccines work by stimulating our immune system to recognize and destroy pathogens we
may be exposed to in the future. Vaccines often consist of killed or attenuated pathogens
that are unable to cause illness. Some modern vaccines employ surface proteins from the
pathogen, which are prepared using standard genetic engineering methods, a strategy that
does not employ the pathogen at all, so are usually much safer than traditional vaccines.
On first exposure to a killed or attenuated pathogen vaccine, the immune system
amplifies specific cells capable of destroying the pathogen and disease from your body.
This first-exposure response takes weeks to develop. Once the initial immune response
has occurred, the immune system “remembers” the pathogen. The next time you
encounter the pathogen, the immune system responds very quickly (faster than the
pathogen can proliferate) and protects you from contracting the disease.
Traditional killed or attenuated pathogen vaccines are prepared in several ways, such as
heating the pathogen or treating it with chemicals like formaldehyde to render it
harmless. There are a number of concerns and dangers to this approach for developing
vaccines:
(1) Heat and chemical killed pathogens often do not resemble the virulent pathogen
closely enough for your immune system to sufficiently recognize the native pathogen.
The resulting vaccine may not provide full protection.
(2) If errors are made in the killing or attenuation process, the vaccine may actually cause
the disease it was designed to prevent with sometimes tragic outcomes.
Jonas Salk had created a vaccine using live polio virus that had been inactivated by
formaldehyde. In the vaccine made by Cutter Laboratories, one of five manufacturers,
virus remained activated. The results, mostly forgotten after more than half a century,
were tragic. Of 120,000 children accidentally given activated poliovirus, 40,000
developed mild polio, but 200 were permanently paralyzed and 10 were killed.27
(3) There are a small number of serious adverse reactions to many vaccines, for example
with the traditional smallpox28 and Bacillus anthracis vaccines,29, 30 although there is
Lynn C. Klotz and Edward Sylvester, “Breeding Bio Insecurity: How U.S. Biodefense is Exporting Fear,
Globalizing Risk, and Making Us All Less Secure.” The University of Chicago Press, October 2009, based
on “Lawsuits Won't Stop Pandemics,” By PAUL A. OFFIT, Wall Street Journal, December 1, 2005
28
J Cono, CG Casey and DM Bell, “Smallpox Vaccination and Adverse Reactions: Guidance for
Clinicians,” Morbidity and Mortality Weekly Report, 2/10/2003
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5204a1.htm
29
GL. Nicolson, Meryl Nass and NL Nicolson, “Anthrax Vaccine: Controversy over Safety and Efficacy,”
American Gulf War Veterans Association http://www.gulfwarvets.com/anthrax5.htm
30
“Detailed Safety Review of Anthrax Vaccine Adsorbed,” Compiled by the Military Vaccine (MILVAX)
Agency US Army Medical Command, February 2009
http://www.vaccines.mil/documents/854AVASafetyRvw.pdf
27
24
controversy regarding the extent of adverse reactions for the anthrax vaccine. These
adverse reactions show up in mass vaccination programs.
(4) Attenuated virus vaccines could pose significant risk to immune-suppressed
populations such as victims of AIDS
New vaccine technologies employ pathogen-mimics or surface proteins that cannot cause
infection or disease, so they pose no danger to patients, laboratory workers, or the
communities surrounding the laboratory. Most research and development of vaccines
using these new technologies may be carried out in BSL1 and BSL2 laboratories since
special precautions are not needed. We highlight some of new technologies simply to
show they have high promise and are completely safe to work with.
Examples of new, safer vaccine technologies
Virus-like particle vaccines
To the immune system, virus-like particles (VLPs) resemble the virus pathogen closely
enough to make effective vaccines. In one method of preparing virus-like particles,
surface protein genes from the pathogenic virus are genetically engineered into a virus
that does not infect humans, such as a baculovirus that infects only insect cells. Once
produced these surface proteins assemble into a structure that closely resembles the
surface of the actual virus.
New vaccines on the market use this technology with great success to target hepatitis B
and human papilloma virus (Sci-B-Vac and GARDASIL, respectively). Also, Rift Valley
fever31, and Chikungunya virus32 have been successfully targeted with VLPs in
preclinical studies. Sci B Vac is produced in mammalian CHO cells, GARDASIL in
yeast.
For Ebola and Marburg filoviruses, virus-like particles using the VP40 Ebola and
Marburg matrix proteins have been produced using the baculovirus system and show high
promise as vaccines.
According to one study
“filovirus-like particles produced by baculovirus expression systems, which are
amenable to large-scale production, are highly immunogenic and are suitable as safe and
effective vaccines for the prevention of filoviral infection.”33
de Boer SM, Kortekaas J, Antonis AF, Kant J, van Oploo JL, Rottier PJ, Moormann RJ, Bosch BJ. “Rift
Valley fever virus subunit vaccines confer complete protection against a lethal virus challenge,” Vaccine.
2010 Mar 8;28(11):2330-9. Epub 2010 Jan 5.
32
W Akahata et al. “A VLP vaccine for epidemic Chikungunya virus protects non-human primates against
infection.” Nature Medicine, Nat Med. 2010 Mar;16(3):334-8. Epub 2010 Jan 28
33
Warfield KL, Posten NA, Swenson DL, Olinger GG, Esposito D, Gillette WK, Hopkins RF, Costantino
J, Panchal RG, Hartley JL, Aman MJ, Bavari S. “Filovirus-like particles produced in insect cells:
immunogenicity and protection in rodents.” J Infect Dis. 2007 Nov 15;196 Suppl 2:S421-9.
31
25
This work was carried out at US Army Medical Research Institute of Infectious Diseases,
where several NEIDL scientists have close ties. Another USAMRIID study tested VLPs
of Ebola and found that they offered 100% protection to monkeys in live challenge
experiments.34
Large scale production systems for proteins using insect cells infected with baculovirus
have been perfected (see for example, http://www.baculovirus.com/). Virus-like particles
are a very active area of research; for example, a search of the medical research database,
PubMed using the search term “virus-like particles” yields close to 3,500 publications
that mention the name.
Chimeric viruses
Non pathogenic viruses modified to carry the genes for a virus-pathogen’s surface
proteins have been shown to be effective as vaccines. Here we provide one example: an
attenuated recombinant vesicular stomatitis virus (rVSV) that makes a glycoprotein from
Marburg virus. Non-attenuated VSV can infect humans causing flu-like symptoms.
When monkeys were vaccinated with rVSV with the Marburg glycoprotein after they had
been exposed to the Marburg virus, the researchers observed:
“[R]hesus monkeys that were treated with the rVSV… as a postexposure treatment
survived a high-dose lethal challenge of MARV [Marburg virus] for at least 80 days.
None of these five animals developed clinical symptoms consistent with MARV.
haemorrhagic fever… [T]hese data suggest that rVSV-based filoviral vaccines might not
only have potential as preventive vaccines, but also could be equally useful for
postexposure treatment of filoviral infections.”35
The example here is also noteworthy as two of NEIDL’s key scientists, Thomas Geisbert
and Joan Geisbert participated in the research. Short of challenge experiments utilizing
the virulent Marburg virus, this research, too, can be carried out at biosafety levels below
BSL4, presumably BSL2.
It is clear from these examples that successful vaccine development to the most
dangerous pathogens can be achieved without increasing the number of individuals with
access to the virulent pathogens. Indeed, it appears that vaccines for Ebola and Marburg
have already been developed.
Bacterial ghosts
Warfield KL, Swenson DL, Olinger GG, Kalina WV, Aman MJ, Bavari S., “Ebola virus-like particlebased vaccine protects nonhuman primates against lethal Ebola virus challenge,” J Infect Dis. 2007 Nov
15;196 Suppl 2:S430-7
35
Daddario-DiCaprio KM, Geisbert TW, Ströher U, Geisbert JB, Grolla A, Fritz EA, Fernando L, Kagan E,
Jahrling PB, Hensley LE, Jones SM, Feldmann H. “Postexposure protection against Marburg haemorrhagic
fever with recombinant vesicular stomatitis virus vectors in non-human primates: an efficacy assessment.”
Lancet. 2006 Apr 29;367(9520):1399-404.
34
26
“Bacterial ghosts,” a concept similar to virus-like particles, is a promising strategy for
developing vaccines for gram-negative bacterial pathogens. (Most bacteria may be
divided into two types, gram-negative and gram-positive bacteria.)
Bacterial ghosts are empty cells of gram-negative bacteria; that is, all the proteins, DNA
and other functional molecules in the bacteria have been drained out, so only the cell wall
remains. Preparation of bacterial ghosts utilizes a protein from a virus called PhiX174,
which invades gram-negative bacteria. PhiX174 enters the bacteria by employing a
protein, called lysis gene E, which punctures holes in the cell wall.
The clever trick to making bacterial ghosts is to genetically engineer the PhiX 174 lysis
gene E into the bacterium which will become the ghost. Quantities of the bacterium can
be grown up under conditions that the lysis gene and a gene for a DNA nuclease to
destroy the bacterium’s DNA are repressed; that is, the genes are not making lysis protein
or DNA nuclease. Like the Trojan horse, when sufficient quantities of bacteria have been
grown, the two foreign genes may be expressed or “turned on” to produce the lysis
protein and the DNA nuclease, resulting in puncture of the cell wall and degradation of
the DNA. All the innards will leak out of the cells leaving only the shell or “ghost” of the
bacterium.
Bacterial ghosts are a promising vaccine technology as the following quotes attest:
“Proof of concept and proof of principle studies showed that BG candidate vaccines are
highly immunogenic and in many instances induce protective immunity against lethal
challenge in animal models… [T]hey are nonliving and devoid of genetic information.
The latter aspect is of great importance for safety…This is an important difference to
other chemical-, heat- and pressure- or radiation-inactivated vaccine candidates, which
also very often need artificial adjuvants to be added to improve their immunogenicity.
The final BG vaccine preparations are freeze dried and are stable for many years at
ambient temperature.”36
An example study of the bacterium Edwardsiella tarda demonstrates that bacterial ghosts
can make more effective vaccine candidates than traditional killed or attenuated bacterial
vaccines. E. tarda is a bacterium that can infect wounds and cause diarrhea in animals.
The authors note:
“[E. tarda ghost]-immunized mice were significantly protected against E. tarda challenge
(86.7% survival) compared to 73.3 and 33.3% survival in the [formalin]-immunized and
[no vaccine control], respectively, suggesting that an [E. tarda ghost] oral vaccine could
confer protection against infection in a mouse model of disease.”37
This study brings up an intriguing possibility, an oral vaccine targeted to the mucosal
immune system, which has biodefense appeal since it can be administered quickly and
Lubitz P, Mayr UB, Lubitz W. “Applications of bacterial ghosts in biomedicine.” Adv Exp Med Biol.
2009;655:159-70.
37
Wang X, Lu C. “Mice orally vaccinated with Edwardsiella tarda ghosts are significantly protected
against infection.” Vaccine. 2009 Mar 4;27(10):1571-8. Epub 2009 Jan 21.
36
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doesn’t require professional administration. An oral vaccine also has appeal in the event
of a natural epidemic caused by a gram-negative bacterium disease, such as plague.
Unlike viruses which are usually specific to one host species, bacteria can infect most
animal species. Furthermore, most bacteria can be studied under BSL2 containment, and
animal challenge studies can perhaps be carried out under BSL3 biocontainment. So there
may not be a need for outsourcing challenge studies.
There is considerable Pub Med literature on ghosts of several gram-negative species,
including B. anthracis, but curiously no reported studies for gram-negative F. tularensis
or Y. pestis, the two Category-A biological weapons agents that BU claims it will
research. Developing bacterial ghost vaccines for these two pathogens should be
considered by BU. The preparation of the ghosts could be carried out at the NEIDL
provided the bacteria require only BSL2 or at most BSL3 containment. We further
suggest that the pathogens employed for the ghosts be attenuated strains to reduce the risk
of infection from a laboratory accident. For most bacteria, attenuated strains are already
available or easy to prepare.
There are no references in Pub Med to ghosts of gram-positive bacteria. A method for
making gram-positive ghosts against B. anthracis should be developed, which could
provide for an interesting basic research project for the NEIDL.
Toll-like receptor agonist vaccines
Vaccines that consist of only one or more pathogen surface proteins suffer from one big
drawback. They often lack potency.
Toll-like receptor (TLR) agonists are molecules that help stimulate immune system cells
to combat pathogens. They act like powerful adjuvants. TLR agonists administered with
or coupled to pathogen proteins or nucleic acids can make for potent vaccines. This is an
exciting new technology that can be used to develop both viral and bacterial vaccines.
A particularly interesting example involves an agonist to a particular toll-like receptor
(TLR-3) that serves as a signal to the immune system for the recognition of doublestranded RNA, the genetic material of the seasonal flu and highly pathogenic bird flu
viruses. A TLR-3 agonist coupled with double-stranded RNA can serve as a broadspectrum vaccine against a number of flu viruses and viruses that mutate frequently to
fool the immune system. The seasonal flu virus is noted for its rapid mutation rate, so
requires a different vaccine each year. The authors of one article conclude
“[T]hese results suggest these TLR-3 agonists have a promising role to play as safe,
effective and broad-spectrum anti-influenza drugs that could complement other antiviral
drugs to combat seasonal, zoonotic and pandemic influenza viruses. The clinical safety of
these drugs and their efficacy in pre-clinical studies may provide sufficient justification
28
for regulatory agencies to consider their fast track development for use in future
outbreaks of pandemic influenza or of other emerging respiratory pathogens.”38
Another scientific paper on a TLR agonist vaccine for the bacterium Mycobacterium
tuberculosis concludes
“A fusion protein… was constructed that consisted of…a potent Toll-like receptor-2
agonist, fused to…a well-characterized immunogenic protein from Mycobacterium
tuberculosis… [M]ice were significantly protected from low-dose aerosol challenge with
M. tuberculosis.”39
Yet another paper may point the way to potent oral or nasal vaccines for gram-negative
bacteria by using the external flagella that bacteria use to swim.
“Gram-negative flagellin, a Toll-like receptor 5 (TLR5) agonist, is a potent inducer of
innate immune effectors…In view of the extraordinary potency of flagellin as an inducer
of… immunity…we evaluated the efficacy of recombinant Salmonella flagellin as an
adjuvant in an acellular plague vaccine. Mice immunized with the F1 antigen of Yersinia
pestis and flagellin exhibited dramatic increases in [immune response]… Importantly,
intranasal immunization with flagellin and the F1 antigen was protective against
intranasal challenge with virulent Y. pestis…, with 93 to 100% survival of immunized
mice. Lastly, vaccination of cynomolgus monkeys with flagellin and a fusion of the F1
and V antigens of Y. pestis induced a robust antigen-specific IgG antibody response.”40
DNA vaccines
Naked DNA can be used as a vaccine. When DNA sequences for pathogen proteins are
injected, the human’s protein production machinery will make the pathogen protein,
against which an immune response develops. Since these short pieces of nucleic acid do
not code for the complete pathogen, they can be safely employed at BSL2.
DNA vaccines are already under development for biodefense, with efforts underway “for
DNA vaccines against several relevant biodefense pathogens: Bacillus anthracis, Ebola
and Marburg viruses, smallpox virus, and Venezuelan equine encephalitis virus.”41
DNA vaccines, if they can be made potent, are ideal for quick response to a newly
encountered pathogen in a biodefense setting. Safety and the ability to evoke the
Wong JP, Christopher ME, Viswanathan S, Dai X, Salazar AM, Sun LQ, Wang M. “Antiviral role of
toll-like receptor-3 agonists against seasonal and avian influenza viruses.” Curr Pharm Des.
2009;15(11):1269-74.
39
Wang B, Henao-Tamayo M, Harton M, Ordway D, Shanley C, Basaraba RJ, Orme IM. “A Toll-like
receptor-2-directed fusion protein vaccine against tuberculosis,” Clin Vaccine Immunol. 2007
Jul;14(7):902-6. Erratum in: Clin Vaccine Immunol. 2008 Sep;15(9):1495
40
Honko AN, Sriranganathan N, Lees CJ, Mizel SB. “Flagellin is an effective adjuvant for immunization
against lethal respiratory challenge with Yersinia pestis,” Infect Immun. 2006 Feb;74(2):1113-20
41
Dupuy LC, Schmaljohn CS, “DNA vaccines for biodefense,” Expert Rev Vaccines. 2009
Dec;8(12):1739-54
38
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necessary vaccine immune response have been demonstrated for at least one biodefense
vaccine, Ebola, in Phase I clinical trails.
“We report the safety and immunogenicity of an Ebola virus vaccine in its first phase I
human study. A three-plasmid DNA vaccine encoding the envelope glycoproteins (GP)
from the Zaire and Sudan/Gulu species as well as the nucleoprotein was evaluated…
Healthy adults, ages 18 to 44 years, were randomized to receive three injections of
vaccine…This Ebola virus DNA vaccine was safe and immunogenic in humans…
Further assessment of the DNA platform alone and in combination with replicationdefective adenoviral vector vaccines, in concert with challenge and immune data from
nonhuman primates, will facilitate evaluation and potential licensure of an Ebola virus
vaccine under the Animal Rule.”42
The authors believe they are well underway to FDA approval under the Animal Rule,
which applies when it is not possible to test vaccine efficacy on humans when statistics
cannot be amassed to demonstrate the effectiveness in preventing disease.
Martin JE, et al., “A DNA vaccine for Ebola virus is safe and immunogenic in a phase I clinical trial,”
Clin Vaccine Immunol. 2006 Nov;13(11):1267-77
42
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Appendix IV. A primer on mucosal immunity
For vaccines that need to be administered to a large population quickly, mucosal
immunity and vaccines targeted to mucosal membranes are of high interest.
“The [m]ucosal immune system is that portion of the immune system which provides
protection to an organism's various mucous membranes from invasion by potentially
pathogenic microbes. It provides three main functions: protecting the mucus membrane
against infection, preventing the uptake of antigens, microorganisms, and other foreign
materials, and moderating the organism's immune response to that material… Because of
its front-line status within the immune system, the mucosal immune system is being
investigated for use in vaccines…”43
Unless we have a wound or some other way into the blood stream, pathogens enter the
body through the mucous membranes.
“The mucous membranes are one of the largest organs of the body... Collectively, they
cover a surface area of more than 400m2 (equivalent to one and a half tennis courts) and
comprise the linings of the gastrointestinal, urogenital and respiratory tracts.”44
The location and extent of our mucous membranes is diagramed in Figure 1.
Figure 1. Diagram depicting the extensive mucous membranes in our body.
The red outlines, which are a little difficult to see, of the orifices and organs depicted in white are the
mucous membranes.
Because of the importance of mucous membranes as the front-line of our immune system
defense, it is surprising that almost all vaccines on the market today and those that appear
to be planned for development in the BU NEIDL are systemic vaccines, not mucosal
vaccines. Systemic vaccines are delivered to the blood stream by injection. Mucosal
43
http://en.wikipedia.org/wiki/Mucosal_immunity
“Mucosal Immunity and Vaccines,” By Robyn Seipp (August 2003) http://www.scq.ubc.ca/mucosalimmunity-and-vaccines/
44
31
vaccines may be delivered orally or nasally, where they activate the mucosal and
systemic immune system cells.
The advantage of nasal or oral delivery in response to a pandemic or bioweapons attack is
obvious, as oral and nasal vaccines can be self-administered in contrast to syringes,
needles, doctors or nurses needed to administer a systemic vaccine.
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Appendix V. Descriptions of new antiviral developments and technologies
Influenza viruses
There are a number of promising neuraminidase inhibitor drugs under development, but
their spectrum of activity is limited to flu viruses, albeit an important class of viruses.
“[T]he near-term flu drug pipeline doesn’t hold many candidates because until recently
the lackluster market offered few incentives for developers.
Nevertheless, a few candidates look promising. Biota is developing long-acting
neuraminidase inhibitors, the most advanced of which is laninamivir…which recently
completed Phase III trials in Japan, Taiwan, Hong Kong, and South Korea…
BioCryst Pharmaceuticals …is preparing for Phase III studies for its antiviral
peramivir…[O]ne dose of peramivir was found to be as effective as a week’s supply of
Tamiflu.45
Other antivirals, while initially targeted to flu viruses, may have wider application.
Several small companies want to be the ones to offer such new approaches. San Diegobased NexBio is developing DAS181, an inhaled viral entry blocker that prevents
respiratory viruses from infecting cells. According to the developers ‘It is a fusion protein
that contains both a sialidase enzyme and a cell-surface-anchoring domain’…
DAS181 could be used therapeutically and prophylactically.46
DAS181 is comprised of two co-joined proteins, as such it may be expensive to
manufacture and may sell for a thousands of dollars, if FDA approved. It is unlikely to be
of value in a natural pandemic or for a large-scale biological weapons attack, because of
cost.
Favipiravir, a broad spectrum antiviral targeting RNA polymerases
One new antiviral drug in discovery, favipiravir (T-705), is generating excitement. It is
about to enter Phase III clinical trials for seasonal flu in Japan.47 Favipiravir works
against flu viruses including H5N1, influenza A, influenza B, influenza C, poliovirus,
rhinovirus, yellow fever virus, respiratory syncytial virus, arenavirus, and West Nile
Virus. 48, 49
Favipiravir works by an entirely different mechanism from the four available antiviral
drugs: it inhibits RNA polymerase, the enzyme necessary to copy the genetic information
45
ibid
ibid
47
“Compound Found to Safely Counter Deadly Bird Flu,” University of Wisconsin-Madison News:
http://www.news.wisc.edu/releases/15718
48
“A new front line drug for flu in the offing?”
49
M Kiso, et al., “T-705 (favipiravir) activity against lethal H5N1 influenza A viruses.” PNAS January 12,
2010 vol. 107 no. 2 882-887
46
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in RNA viruses to make new virus copies. It does not inhibit DNA synthesis, so does not
work on DNA viruses; and more importantly, it does not interfere with the copying of
human DNA, which would make it toxic to us. Indeed, it appears quite safe in humans.
LJ001, a broad-spectrum antiviral targeting entry
“LJ001 [is] effective against numerous enveloped viruses* including Influenza A,
filoviruses, poxviruses, arenaviruses, bunyaviruses, paramyxoviruses, flaviviruses, and
HIV-1. In sharp contrast, the compound had no effect on the infection of nonenveloped
viruses. In vitro and in vivo assays showed no overt toxicity. LJ001 specifically
intercalated into viral membranes, irreversibly inactivated virions while leaving
functionally intact envelope proteins, and inhibited viral entry at a step after
virus binding but before virus–cell fusion. LJ001 pretreatment also prevented virusinduced mortality from Ebola and Rift Valley fever viruses.”50
*In addition to their protein coat or capsid, some viruses have a lipid “envelope derived
from the host cell membrane covering the capsid.
Some scientists on this project are from Ft. Detrick and Harvard Medical School, so again
NEIDL scientists have a connection.
RNA interference
RNA interference (RNAi) is a mechanism in human cells that interferes with the process
of making proteins from genes by recognizing and degrading the messenger RNA coded
by the genes. The drug class is called small interfering RNAs (siRNA). RNA interference
is a normal means for controlling what proteins are to be made in a particular human cell
at a particular time. RNA interference has also been postulated to be an ancient anti-virus
defense mechanism.
siRNA drugs can be readily synthesized to bind to and destroy messenger RNAs from
invading viruses. Since the messenger RNA sequences are known for most important
viral pathogens and bioweapons agents, siRNA drugs can be developed against these
pathogens on short notice. This rapid response capability is of special interest for rapidly
emerging diseases such as pandemic flu viruses. The technology allows for development
of drug candidates without requiring live pathogen, so development can be carried out in
BSL1 and BSL2 laboratories.
In a recently published paper in The Lancet51, an RNAi drug was shown to protect
macaques from Ebola infection.
“Two (66%) of three rhesus monkeys given four postexposure treatments of the pooled
anti-ZEBOV siRNAs were protected from lethal ZEBOV [Zaire Ebola virus] infection,
MC Wolf, et al., “A broad-spectrum antiviral targeting entry of enveloped viruses.” PNAS Early Edition
www.pnas.org/cgi/doi/10.1073/pnas.0909587107
51
TW Geisbert, et al. “Postexposure protection of non-human primates against a lethal Ebola virus
challenge with RNA interference: a proof-of-concept study,” The Lancet, Volume 375, Issue 9729, Pages
1896 - 1905, 29 May 2010
50
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whereas all macaques given seven postexposure treatments were protected. The treatment
regimen in the second study was well tolerated with minor changes in liver enzymes that
might have been related to viral infection…This complete postexposure protection
against ZEBOV in non-human primates provides a model for the treatment of ZEBOVinduced haemorrhagic fever. These data show the potential of RNA interference as an
effective postexposure treatment strategy for people infected with Ebola virus, and
suggest that this strategy might also be useful for treatment of other emerging viral
infections.”
Although the study was modest, involving only seven macaques, it demonstrates the
promise of RNAi drugs.
The main author’s, Thomas Geisbert, institutional affiliations are listed as National
Emerging Infectious Diseases Laboratories Institute, Boston University School of
Medicine; Department of Microbiology, Boston University School of Medicine; and
Department of Medicine, Boston University School of Medicine.
Just across the river from the NEIDL in Cambridge, Alnylam Pharmaceuticals, a leading
RNAi company, is headquartered. Among its many drug discovery and development
programs, Alnylam has an early-stage collaboration to develop an RNAi drug against
Ebola virus. According to the Company’s website
“The NIAID, a division of the National Institutes of Health (NIH) awarded Alnylam a
$23M contract to develop an RNAi anti-viral therapeutic against the Ebola virus.”
It is unclear whether BU’s NEIDL and Alnylam are working together as the funding for
the work reported in The Lancet is from the Defense Threat Reduction Agency, not NIH.
NEIDL can also take advantage of its proximity to the lab of Craig Mello, who received
the Nobel Prize for the discovery of RNAi. He currently heads a group at University of
Massachusetts Medical School in Worcester.
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