Volume V, Number 2 Sabin Summer 2002 EPORT The newsletter of the Albert B. Sabin Vaccine InstituteR —dedicated to disease prevention www.sabin.org

Nation’s Physicians Sign SVI Open Letter on Vaccine Safety Misinformation Threatens Children’s Health Warn Top Doctors

Leading physicians joined the Sabin munize them,” he said. “Parents need vaccine. “But I also don’t want mine to Vaccine Institute and a virtual “who’s to know that are the be the one in 10 that dies if they get the who” of the medical, academic and ad- greatest weapons we have against disease; I’d rather take my chances with vocacy community to recognize National deadly, preventable illnesses.” the one in 3 million than the one in 10,” Infant Week this past April Concern over confusing media cov- remarked Ms. Walther. with the release of an Open Letter em- erage, widespread Internet misinforma- Sabin Scientific Advisory Council phasizing the critical role of in tion, and the risk of falling immunization Chair , MD, PhD, who is protecting public health. rates prompted more than 100 of the chairman of Microbiology and Tropical The Open Letter on Vaccines was nation’s top physicians and public health Medicine at GW Medical Center, urged announced at a press briefing at the experts to sign the open letter publiciz- parents who had concerns about immu- Children’s National Medical Center in ing their strong, unwavering support for nizing their child to talk to their pediatri- Washington, D.C. Peter Holbrook, MD, vaccines. cian or to seek information from cred- chief medical officer, welcomed the A Tennessee mother, Suzanne ible websites like those sponsored by the media and visitors to the hospital and Walther, delivered a message to parents , Centers for Dis- ceremoniously signed a poster-sized rep- during the announcement of the Open ease Control and Prevention, American lica of the signatories list. Letter. She chose not to vaccinate her Academy of Pediatrics, or the National One of the strongest endorsements for daughter after reading misinformation Network for Immunization Information. the statement came from Louis Z. Coo- about vaccines. Her daughter subse- Physicians and health experts around per, MD, president of the American quently developed a form of meningitis the country are encouraged to sign the Academy of Pediatrics, who also was that would have been prevented by im- letter by visiting www.sabin.org. The on hand. “The single most important munization. Sabin Vaccine Institute has set a goal of thing parents can do to protect their chil- “I don’t want my child to be the one adding hundreds of signatures to dem- dren against infectious diseases is to im- in 3 million” who has a reaction to a onstrate the overwhelming support for vaccines within the medical and public health community. The Open Letter on Vaccines and the signatories to date can be found on pages 8 and 9 of this newsletter. I nside Communicating the Value of Vaccines ...... 2 Chairman’s Message ...... 3 Parasitology Grant Review ...... 4 Supply Needs Shot in the Arm ...... 5 New Vaccine Developments ...... 6 Open Letter on Vaccines List of Signers ...... 8 SVI Scientific Meeting on Vaccines and Bioterrorism ...... 13 Peter Holbrook, MD, left, chief medical officer at Children’s National Medical Center in Washington, D.C., joins Louis Cooper, MD, president of the American Academy of Pediatrics, and Peter Hotez, MD, PhD, of New Book Release ...... 14 George Washington University and the Sabin Vaccine Institute, as a signatory of the Open Letter on Vaccines. Sabin Vaccine Institute Annual Dinner ...... 15 2 SUMMER 2002 SABIN VACCINE REPORT

The Sabin Vaccine Report VIEW is published by the POINT Albert B. Sabin Vaccine Institute Subscriptions are free Communicating the Value of Vaccines Please direct inquiries to: Reliable Information is the Critical Component Vaccines are some of the greatest miracles pointed a penetrating light on the lack of SABIN VACCINE REPORT of modern science. They set up a powerful scientific rigor of those who would challenge 58 Pine Street New Canaan, CT 06840-5408 immune response in the body against diseases the safety of vaccines. The study reviewing 22 phone: 203.972.7907 that otherwise could imperil one’s health or anti- Web sites revealed that most fax: 203.972.4763 that of an entire community. Vaccines available of them focused on concerns about www.sabin.org today protect against preventable and once- governmental abuses, alternatives to email: [email protected] common childhood diseases, like measles, vaccination, and vaccine safety and mumps, chicken pox, and polio, and from effectiveness. The study concluded that the EDITOR Raymond MacDougall frightening biological agents, including concerns expressed on these Web sites about ASSOCIATE EDITOR COPY EDITOR smallpox and anthrax. But be assured, for vaccine safety were largely unsupported by Veronica Korn David Bedell everyone’s protection, long before any vaccine peer-reviewed scientific literature. OFFICERS OF THE SVI BOARD OF TRUSTEES is recommended for broad use, it undergoes A coincident survey reported in the H. R. Shepherd, Chairman rigorous testing for safety and effectiveness. Archives of Disease in Children should make William R. Berkley, Co-Chairman Although there are extremely rare instances all of us think twice before we blindly accept Michael E. Whitham, Esq., Secretary/ of serious adverse reactions to vaccines, they what we read on the Web. It indicated that Treasurer have a demonstrated record of safety and are 43% of the links found by Internet search SVI STAFF held to the highest standard. engines point to sites that oppose the Fran G. Sonkin, Executive Vice President Public health experts have had an uphill vaccination of children. This is sobering data, Paul J. Vilk, RPh, RAC, Vice President, battle lately convincing the population here considering that some estimates are that 55% Program Management and Regulatory and abroad about the safety and effectiveness of adults with Internet access use it to seek Affairs, Initiative Raymond MacDougall, Director of of vaccines. For the past year, inspired by a health information one time or another. Communications scientifically questionable study, MMR It would be a tragedy to forget the real pain Veronica Korn, Research Associate vaccination rates in England plummeted. A and suffering caused by the diseases that are David Bedell, Executive Assistant to recent report in the British journal, Clinical now preventable as a result of vaccines. In the Chairman Evidence, did much to put to rest the specter the case of measles alone, immunization has Vanessa Santiago, Assistant to the of a link between the measles, mumps, and cut the incidence of the disease by 99.9%— Executive Vice President (MMR) and autism. Hopefully, elsewhere around the globe, measles kills Gboku Lumbila, Executive Assistant, the publication of the comprehensive 950,000 people each year in countries Hookworm Vaccine Initiative government-sponsored study exonerating the without comprehensive immunization. Jean-Serge Valcourt, Accounting MMR vaccine will change the actions of many Parents should speak to their child’s Christel Lane, Receptionist/Staff Assistant Edward Smith, Information Coordinator Britons who had deferred vaccinating their pediatrician to get good information about and Librarian children, and will prevent similar fears here the risks and benefits of vaccines, or carefully in the United States. select the Web sites where they gather their SVI ADVISORS Philip K. Russell, MD, Senior Advisor to In recent years, a movement of opposition information. Our children should never suffer the Chairman to vaccines has propagated frightening and the consequences of preventable diseases. Peter J. Hotez, MD, PhD, Senior Fellow unfounded claims associating vaccines and One thing is for certain—vaccines have & Chair, Scientific Advisory Council harmful effects. As a result, many parents saved millions of lives and continue to be the William Muraskin, PhD, Sabin Fellow seeking factual and helpful information about world’s most humane and cost-effective Patricia Thomas, Sabin Fellow immunizations have been misled. In their medical intervention against preventable Nancy Gardner Hargrave, Development concern for the well-being of their children infectious diseases. We only hope that vaccine Counsel or themselves, many people have turned to science is able to achieve even greater things the Internet, where anti-vaccination sites in years to come in the war on AIDS, cancer, abound. It takes the dogged efforts of the malaria, tuberculosis, and hookworm scientific, regulatory, and academic throughout the world. communities to correct the misinformation —by H.R. Shepherd and offer scientifically founded data as a reassuring alternative. H.R. Shepherd is Chairman of the A study published this June in the Journal Sabin Vaccine Institute. of the American Medical Association dedicated to disease prevention www.sabin.org 3 Taking a Long, Hard Look at the Vaccine Supply Question A Message from the Chairman The Sabin Vaccine Institute ♦ Financial incentives do not exist for manufacturers to is taking on the issue of vac- market medically necessary but unprofitable vaccines. cine supply as a matter that ♦ Current vaccine production capacity does not meet concerns individual, domestic, long-term needs, to say nothing of surge capacity in the and global well-being. That event of a bioterror incident. Government programs fail vaccines have been devised to ensure an adequate long-term stockpile of necessary to combat many of the vaccines. world’s worst diseases is not ♦ Low reimbursement has driven many physicians out of sufficient security, particularly the delivery system; consequently, immunization is un- if the supply of vaccines is even and uncoordinated. jeopardized by insufficient ♦ H.R. Shepherd, Chairman Divergence of vaccine products between the U.S. and production or overly burden- developing countries destroys economies of scale, nega- some regulations. In October tively impacting issues of tiered pricing and profitability th 2002, the Institute will hold its 9 Annual Vaccine Policy Col- in developing country markets and lessening availability loquium at Cold Spring Harbor Laboratory in New York, where of routine vaccines. an assembly of scientific and public health experts from in- These problems are occurring on a global scale, and are dustry, government and international organizations will bring further compounded by the urgent need to immunize the poor- their unique perspectives to this year’s theme: vaccine sup- est populations of the world and to develop “orphan vac- ply. cines” for diseases that are not common to developed na- There have been significant shortages of childhood vac- tions. Furthermore, the events of fall 2001 highlighted the cines around the world—in the United States alone, 8 of 11 shortage of vaccines for defense against biological warfare vaccines have been in short supply during the latter months agents such as smallpox and anthrax. of 2001 and into the first half of 2002—and demand for adult We have identified the issues and, in October, will certainly immunizations also has exceeded supply, raising concern on examine them in depth. A forward-thinking process funda- a global scale about the ability of the system to handle poten- mental to our meeting at Cold Spring Harbor is necessary to tial disease threats. Why have these situations developed? solve these issues. I welcome your feedback as we make We can make the following observations about the present preparations for our colloquium. Also, I would ask that you system: continue to provide us with your thoughts on issues you would ♦ There is insufficient collaboration and communica- like to see the Sabin Vaccine Institute cover in its various tion among federal agencies and among companies, fur- forums—either in publication or in a meeting we may con- ther burdened by a complex, lengthy, and unpredictable vene. Thank you for your ongoing support. regulatory approval process. ♦ Vaccine manufacturing and production is a complex Sincerely, process with stringent quality control. ♦ Manufacturers sometimes abruptly leave the market- place when the return on investment of a vaccine is no longer considered profitable. Meanwhile, though the num- Chairman ber of vaccine manufacturers has declined, the number Sabin Vaccine Institute of vaccines has increased.

Notable Quote— Would you like to Would you like to Benjamin Franklin’s Advice on Immunization: read the Sabin Vaccine Report “In 1736 I lost one of my sons, a fine boy of four years old, by the small-pox, taken in the common way. I long regretted bitterly, and still regret that I had not given it to him by online? Our news- . This I mention for the sake of parents who omit that operation, on the letter is available supposition that they should never forgive themselves if a child died under it; my in a PDF format at example showing that the regret may be the same either way, and that, therefore, the www.sabin.org. safer should be chosen.” Benjamin Franklin: Writings, The Autobiography, ed. J.A.L. Lemay, The Library of America, 1987, p. 1402. 4 SUMMER 2002 SABIN VACCINE REPORT Hotez Leads Review of Chinese Parasitology Grant June Trip Follows Four Years of Discovery on Hookworm, Malaria, and Trichinosis Hookworm, malaria, and trichinosis million Bill and Melinda Gates Founda- covery of a new gene family from Plas- are each diseases that originate from tion grant. modium sp. that exhibits homology to parasitic . A unique grant from Approximately 20 Chinese scientists intracellular trafficking proteins known the Chinese Medical Board (CMB) of who participated in CMB Parasitology as dynamins; and application of New York has for the past four years Grant-sponsored research convened for proteomics to the discovery a new fam- supported researchers at institutions in the one-day meeting to review scientific ily of surface proteins known as malaria China and the United States in collabo- progress obtained over the period from surface reactive . The ration on investigations into how to pre- 1998 to 2001 and to discuss future di- proteomic approach is now been sub- vent each of these serious diseases. rections for research activities. Hotez mitted for international patents. “It is Their investigations, including work that led the review with Cohava Gelber, PhD, exciting work,” says Hotez, who believes also is supported by the Sabin Vaccine MBA, a mo- it will merit journal publi- Institute, have led to promising discov- lecular immu- NEWS FROM cation. The method might eries that may ultimately lead to vac- nologist spe- THE BENCH also offer promise for the cines cializing in de- development of other mi- Peter Hotez, MD, PhD, Sabin Scien- velopment of new vaccine platform crobial vaccines, according to Hotez. tific Advisory Council chairman and technologies and senior vice president Beijing’s Capital University of Medi- chairman of Microbiology and Tropical of Pharmaceutical Discovery Corpora- cal Sciences is the site of research for a Medicine at The George Washington tion of Elmsford, New York. vaccine to prevent trichinosis, a para- University, met this past June in China An impressive body of scientific data sitic nematode infection passed to hu- with colleagues working on vaccine de- has been compiled as a consequence of mans by exposure to raw or the funding, including undercooked meat. Emphasis by the in- the discoveries of new vestigative group focuses on an important vaccine an- known as Ts87. Some of this work was tigens for malaria, done in collaboration with Zhan Bin, trichinellosis and hook- MD, of the Institute of Parasitic Dis- worm. In the last eigh- eases in Shanghai and Dr. Hotez at The teen months, new ef- George Washington University. forts were made to re- The Institute of Parasitic Diseases, engineer these antigens Shanghai, reported on the status of their for appropriate vaccine progress in hookworm research. Pro- delivery. The group dis- fessor Xiao Shuhua is the lead investi- cussed strategies for gator on this project while Zhan Bin translating the major works in the United States on the hook- discoveries into papers worm vaccine project sponsored by the for peer-reviewed in- Sabin Vaccine Institute. Xiao also heads ternational scientific an NIH-sponsored Tropical Medicine journals, and it antici- Research Center project to examine the On a tour of Beijing are participants in the Parasite Grant review of the pates the publication of genetic diversity of hookworm. With Chinese Medical Board of New York. From left, Zhu Xin Ping, Wang a number of manu- help from CMB funding, Xiao’s group Heng, Cohava Gelber, Peter Hotez, and Xiao Shu Hua. scripts submitted to top has now developed a model of vaccine tier journals including , explored leishmanization as a velopment funded by the CMB Parasi- Nature Biotechnology, Infection and platform technology, and made progress tology Grant. The meeting was con- Immunity, and TheJournal of Biologi- in the area of gene discovery. ducted in Beijing, at the Peking Union cal Chemistry. According to Hotez, the reviewers Medical College, School of Basic Medi- Peking Union Medical College, agreed that the productivity of the re- cal Sciences. Hotez is a parasitologist Beijing, is the site of research on ma- search sponsored by the CMB Parasi- and infectious disease pediatrician spe- laria molecular biology and vaccine de- tology Grant has been extremely high. cializing in developing vaccines for hel- velopment under the Parasite Grant. The The outcome of this research could have minth infections. He leads the Sabin- investigators reported progress in three major impact both throughout China and supported Hookworm Vaccine Initiative, major areas: development of a hepatitis globally, and serves as a model of inter- which also receives funding from an $18 B core antigen platform technology; dis- national scientific cooperation. dedicated to disease prevention www.sabin.org 5 Vaccine Supply Needs a Shot in the Arm Harvard Medical School Student Warns Against Taking Vaccines for Granted

The following article was written by Erica Seiguer, a third-year senal against major child- change in FDA requirements or the need MD, PhD student at Harvard Medical School. Ms. Seiguer for- hood diseases and have to upgrade a plant can, and has, led to merly served as a research fellow at the Sabin Vaccine Institute. raised concerns of out- shortages. Lack of coordination be- The article is reprinted from FOCUS, News from Harvard’s Medi- breaks of diseases not tween public and private sectors. Vac- cal, Dental, and Public Health Schools. seen in decades. In the cines are purchased and supplied wake of recent concern through a complex network of public and Most of us seem to take vaccines for over preparedness for possible private providers. While approximately granted. We go about our business pro- biowarfare, the inadequacies of the cur- 52 percent of vaccines for U.S. children tected from some of the most dread dis- rent system have been brought to the are purchased with federal funds, the eases of mankind—polio, measles, diph- forefront. rest are privately purchased (often by theria, and even smallpox—without con- Ills of the System. Declining num- individual physicians or group practices). cern for contracting them. By the time ber of vaccine manufacturers. The The 2000-2001 flu vaccine shortage our children enter school, they’ve re- private sector is primarily responsible for highlighted a worrisome failure to en- ceived between 16 and 20 . research and development, and manu- sure that high-risk individuals were im- We feel confident that they won’t come facturing and delivery of vaccines. munized first. According to an audit by home from school with anything more There are currently only four major vac- the General Accounting Office, there threatening than a minor infection com- cine manufacturers in the world, and was no formal mechanism in place to mon in childhood. In recent years, how- only two in the U.S. Twenty years ago ration the available vaccine to those most ever, shortages of critical vaccines have there were approximately four times as in need. In this case, according to the highlighted the fragile nature of the U.S. many firms. In 1979, eight American GAO’s findings, doctors were not able vaccine supply and distribution system. pharmaceutical companies held 70 per- to secure vaccines for at-risk elderly pa- A variety of factors are thought to have cent of all licenses for vaccines in this tients, while supermarkets were able to contributed to widely publicized short- country while foreign companies and offer free or low-cost flu shots to cus- ages of in the 2000- institutes held 17 percent, with the re- tomers. The antivaccine movement. 2001 flu season, and recent shortages maining 13 percent held by state labo- The growth in the antivaccine movement in childhood vaccines preventing diph- ratories and a university. Lower profits in recent years has had an impact on theria, tetanus, whooping cough, polio, in the vaccine industry in relation to the vaccine industry, as well as the pub- Haemophilus influenzae, chickenpox, other pharmaceutical operations. lic health sector. Fears concerning side measles, mumps, rubella, and invasive Vaccine revenues make up only a small effects of immunization (for example, pneumococcal disease. The declining fraction of the pharmaceutical industry’s autism with the MMR vaccine) as well number of vaccine manufacturers, low revenues, an estimated 3.5 percent. as some parents’ desire not to vaccinate profits in the vaccine area compared While newer vaccines and those in the their children and highly publicized con- with other pharmaceuticals, federal pipeline may bring greater revenues to cerns about mercury in vaccines have regulations, lack of coordination be- the industry, the pharmaceuticals mar- required an aggressive public awareness tween public- and private-sector provid- ket is much more profitable compared campaign by the public health commu- ers, and a growing antivaccine move- to vaccines and other biologics. Federal nity. This campaign has been gaining mo- ment have all been cited as indicators regulation of vaccines. The vaccine mentum in the past several years, lead- of a failing system. As of April 2002, industry is regulated by the Center for ing to the creation of several organiza- there were shortages of DTaP, IPV, Hib, Biologics Evaluation and Research tions responsible for communicating both varicella, MMR, and pneumococcal vac- (CBER) of the Food and Drug Admin- the risks and benefits of immunizations. cines, prompting revisions in current istration. CBER evaluates each vaccine Cures to Come? Why should we vaccine recommendations and rationing candidate and either accepts or rejects worry about an unstable vaccine sup- of childhood vaccines. Together these applications to license the vaccines. ply? Vaccines are critical to the preven- vaccines constitute a public health ar- Each vaccine manufacturing plant must tion of infectious diseases and are often be licensed separately, and the FDA considered the underpinning of our pub- The Sabin Report seeks to enrich the current regularly inspects facilities to ensure high lic health system. The enormous decline dialog on vaccine research and policy with ar- quality of the product. After licensure, in infectious diseases due to vaccines ticle and review contributions. Opinions ex- the FDA continues to monitor the vac- and the reduction in attendant morbidity, pressed in the articles are those of the authors cine and manufacturing facilities as long mortality, and financial cost is remark- and do not necessarily represent the position as a manufacturer holds a license. In able. Yet due to their often invisible ef- of the Institute. the case of single-source vaccines, a Continued on page 14 6 SUMMER 2002 SABIN VACCINE REPORT Exploring New Vaccine Development Gregory Poland and Colleagues Undertake an Assessment of Vaccine Science

agent, resultingin immunity against the Vaccines are hailed as one of the most impor- sertedDNA) undergoes limited replica- tion, the protein of interest is produced, foreign organism replicating and estab- tant public health achievements of the 20th century.1 In the next five to 15 years, new vac- and the host develops an immune re- lishing an infection. A therapeutic vac-

cines and new vaccine delivery technology will sponse against the protein. cine, however, can limit or eradicate an fundamentally change how clinicians prevent In a related strategy, so called naked already present and established infec-

and treat disease, with a substantial impact on DNA is injected directly into the host to tious agent or condition.The development public health. This review describes recent de- produce an immune response (fig 1). of therapeutic vaccines has depended

velopments in the basic science underpinning Naked DNA is simply sequences of DNA in part onthe ability of DNA vaccination

the development of new vaccinesand summa- inserted into bacterial plasmids (simple, to induce both humoral and cellmediated rizes the potential of these vaccines to treat immune responses by inoculation of plas- extrachromosomal rings of DNA found and preventa wide range of infectious and non- mid DNA containingsequences for tran- 2-5 in bacterial cells) and injected into the infectious diseases. Inaddition, research is scription and translation, resulting in the being carried out on much needed vaccines host. These have been effective in ani- for the developing world for diseases such as mal models, but intramuscularly injected in vivo synthesis of an immunogenic

malaria, hookworm, dengue, enterotoxigenic DNA in humans has failed to generate peptide orprotein. Escherichia coli, shigella, and tuberculosis, vigorous immune responses, although Attempts are being made to develop but these are beyond the scope of this brief transdermal or intradermal delivery of a therapeutic vaccine against HIV that review. DNA has been more encouraging. A will induce virus-specific cytotoxic T

of transdermally delivered lymphocytesagainst HIV, with the goal Methods. We searched PubMed and Medline data- microscopic gold beads coated with of having activated T cells destroy la- bases (1995-2001), as well as our own libraries, for tently infected cells. Other efforts in- DNA coding for hepatitis B surface an- articles of relevance to this brief review. tigen generated protective levels of an- clude developing therapeutic vaccines 6 against Helicobacter pylori, mucosal New Vaccines against tibodies to the antigen. This vaccine has

infectious diseases also generated CD8 cytotoxic lympho- candidiasis, herpes viruses, and human cytes.6 Although efforts have been suc- papillomavirus. DNA vaccination for Development of DNA vaccinesvaccines. One ap- cessful in animal models of vaccines hepatitisB virus has shown great prom- proach generating great interest is that against several pathogens, progress in ise. The delivery of viral DNA se- of inducing protective immune responses humans has quencescan induce longlasting humoral by injecting engineered DNA sequences been much and cell mediated immunity in micein- from infectious organisms against which 8 9 slower. To date, fected with hepatitis B virus. In protection is desired. If an antigen can only DNA vac- transgenic mice, at least, there is a de- be identified it is possible to insert the cines against crease in or clearance of the hepatitis B DNA sequence coding for the protein hepatitis B6 and surface antigen, with evidence of induc- antigen into a carrier genome (such as malaria7 have tion of antibodies and proliferation of several of the poxviruses or 10 induced immune CD4 T cells. Clearly, the capabilities alphaviruses). Once delivered into the responses ofthe immune system to eliminate an in- host, the organism (and hence the in- thought to be fectious agent even

after an infection or protective inhu- Fig 1. Principle of disease is established This article is by Gregory A Poland, mans. DNA vaccination. An chief a, Dennis Murray, senior immunogenic gene is could substantially Development of inserted into an research fellow b, Ruben Bonilla- improve human therapeutic vac- expression plasmid Guerrero, senior research fellow a. health. cines. Traditional (A), which is inserted It is reprinted with permission of the into cultured cells (B). Other important authors and the British Medical vaccination is examples of thera- The cells are Journal. It first appeared in the journal the preventionof screened for peutic vaccine devel- on June 1, 2002, 324:1315-1319. a specific infec- expression of the opment include the gene protein and then a tious disease by development of vac- Mayo Vaccine Research Group, cultured. The plasmid 611C Guggenheim Building, Mayo delivering an im- cines against certain DNA is then extracted Clinic and Foundation, 200 First munogenicanti- from the cells and cancers,11 which is Street, SW, Rochester, MN gen derived purified before being discussed later. 55905, USA, b Department of from the surface used to immunise a of the infectious host (C) Continued on page 7 dedicated to disease prevention www.sabin.org 7

(antigenic drift), protection of high risk Advances in current vaccines individuals requires annual vaccination. Summary points ♦ A live attenuated influenza virus vac- New prophylactic and therapeutic The bacterium Streptococcus cine being proposed for US approval vaccines will prevent and potentially pneumoniae and influenza viruses ac- cure disease by providing people with contains recombinant cold-adapted count for considerable morbidity and the necessary immunological tools strains of influenza A and B and is given mortality worldwide. Now approved in ♦ Advances in current vaccines such by intranasal spray. Several studies have several Western countries, S as conjugated pneumococcal vac- examined the use of live attenuated in- cines for adults, nasal spray vaccines pneumoniae conjugate vaccines should fluenza vaccines in children and adults.12- for influenza, and adult acellular per- help reduce the number of cases of in- 14 In seronegative children more than tussis vaccines will provide an efficient vasive S pneumoniae disease way to produce longlasting protective 15 months old antibody responses to the (bacteraemia, meningitis, and sepsis) in immunity influenza A and B components after a infants and young children. A live, at- ♦ Development of vaccines against single dose of vaccine indicated an over- tenuated influenza virus vaccine is near- non-infectious diseases (such as can- all efficacy of 93%.12 Use of a live at- cer, diabetes, and Alzheimer’s disease) ing approval in the United States. This tenuated trivalent vaccine in adults sig- and nicotine and cocaine dependence vaccine, administered as an intranasal nificantly reduced the occurrence of ill- will provide alternative treatments spray, should stimulate both systemic and ♦ ness, visits to healthcare providers, and Vaccines against biological weap- mucosal immunity, while decreasing re- ons will be possible by advances in days of work lost.14 liance on the use of parenteral injections DNA vaccines ♦ (see box for a list of potential vaccines). New vaccines against New vaccine delivery technology Streptococcus pneumoniae. Multivalent non-infectious diseases will provide easier delivery routes (such polysaccharide vaccines for S as transcutaneous, depot, nasal, and When correctly targeted, an immune oral delivery) without compromising pneumoniae have been available in the response can be used to eliminate cells efficacy United States since 1977, but they pro- with aberrant behaviour (dysplasia) or duce a poor or inconsistent immune re- aberrant genomic function (malignancy) an immune response that could specifi- sponse in children, especially those less 18 or to reduce the amount of inflamma- cally target and eliminate tumour cells. than 2 years old. Polysaccharide vac- tion affecting a specific organ (such as Other efforts include therapeutic vac- cines induce antibodies primarily by in diabetes). 15 16 This raises the possi- cines against melanoma, colorectal can- mechanisms independent of the T cells 19 20 bility of developing vaccines against dis- cer, leukaemia, and other cancers. and are not long lasting and do not in- eases not known to be related to infec- The ability of DNA vaccines to deliver duce an immune memory response. For tious agents. Two of the most exciting precise and specific nucleotide se- these reasons, a protein carrier conju- and promising areas in this regard are quences representing target genes— gated to a polysaccharide antigen of S vaccines against cancer and autoimmune such as the ALVAC gp100 gene for pneumoniae has now been developed, diseases. melanoma and the ALVAC CEA-B7.1 which causes the immune response to gene for colorectal cancer—and specific be T cell dependent, allowing infants and Cancer. The identification of specific tu- protein fragments such as the HER2/ children to respond better to the vac- mour antigens (tumour associated anti- Neu peptide found in breast cancer cells cine. The US licensed heptavalent S gens) that are present only in cancer 21 22 have been studied as a potential pneumoniae conjugated polysaccharide cells—such as those found in leukaemia, means with which to induce an immune vaccine contains the seven serotypes breast cancer, melanoma, prostate can- response. 19 23 (4, 6B, 9V, 14, 18C, 19F, and 23F) most cer, and colon cancer—provide immune commonly associated with invasive dis- targets for which immunogenic vaccines Autoimmune diseases. Diseases related ease among infants and young children. may conceivably be designed. For ex- to pathological immune activation,such The new vaccine is also expected to ample, the expression of protein GPI-B7- as autoimmune diseases and allergies, have the benefit of reducing nasopha- 1 transferred onto membranes from a might be treatable or preventable with ryngeal carriage of these seven S murine thymoma tumour cell protects vaccines. Efforts are being made to de- pneumoniae serotypes. mice against this kind of tumour.17 In velopvaccines against rheumatoid arthri-

humans it is possible to stimulate T cell tis, multiple sclerosis, myastheniagravis, Influenza virus. The only influenza vac- responses using isolated membranes sur- food allergies, and especially type 1 dia- cines currently licensed in the United gically removed from human tumour tis- betes because of its associated substan-

States are parenteral inactivated influ- sues that express major histocompatibil- tial morbidity andmortality. enza virus vaccines prepared in chick ity complex (MHC) class II molecules, In the case of type 1 diabetes, lym- embryos. Because of changes in the in- suggesting the possibility of establishing phocytes infiltrate the pancreatic islets fluenza viruses circulating each year Continued on page 10 8 SUMMER 2002 SABIN VACCINE REPORT

Richard F. Corlin, MD President, American Medical OPEN STATEMENT ON VACCINES Association Stephen Crane, PhD We, the undersigned, support immunization as the safest, most effective way to control and eradicate infectious Executive Vice President and CEO diseases. Infectious diseases were once prevalent in the United States, inflicting widespread suffering and death American Academy of Physician Assistants on young and old, rich and poor alike. Deadly diseases such as smallpox, polio, diphtheria and measles have, Janet L. Cranshaw, MD for the most part, become distant memories. Most of the credit goes to vaccines, medical miracles that many General Pediatrician, New York take for granted. James Curran, MD, MPH Dean, Rollins School of Public Vaccination eradicated smallpox but the other diseases still exist. Without immunization, they quickly can return Health, Emory University and cause widespread harm, as the examples below demonstrate. Although there are extremely rare instances John David, MD of serious adverse reactions to vaccines, vaccines have a demonstrated record of safety and are held to the Professor, School of Public Health highest standard. Vaccines are rigorously tested for safety and effectiveness before licensure by the Food and Harvard University Drug Administration, and their safety and purity are continuously monitored. Ciro de Quadros, MD, MPH Director, Division of Vaccines & Childhood and adult infectious diseases pose a real threat to personal and public health. Those who are not Immunization, Pan American vaccinated leave not only themselves, but others, vulnerable to dangerous diseases. Vaccines are the most Health Organization Vincent Devita, Jr., MD effective option for preventing and stopping the spread of infectious diseases. Director, Cancer Center, Yale Vaccines Save Lives University Molly Droge, MD ♦Immunization has cut measles incidence in the U.S. by 99.9%. Vaccination still is important——measles kills General Pediatrician, Dallas Texas 950,000 people each year in countries without comprehensive immunization. Kathryn Edwards, MD Professor of Pediatrics, Vanderbilt ♦Immunization wiped out smallpox in 1979. Before smallpox was eradicated, it killed over 300 million people University Medical Center in the 20th Century——more than all wars combined. Ann M. Endy Infection Control Practitioner, ♦Vaccination eradicated paralytic polio from the Western Hemisphere. Before a vaccine was available, Children’s Hospitals and Clinics, polio affected as many as 57,000 Americans per year with paralytic disease. Minneapolis ♦ Howard Faden, MD Without routine vaccination, infectious diseases can quickly return and cause widespread harm. In Russia, Professor of Pediatrics, SUNY diphtheria cases jumped from 900 in 1989 to 50,000 in 1994 after a drop in vaccination rates. Buffalo ♦ Edmond H. Fischer Immunization has nearly eliminated a major cause of childhood meningitis, Haemophilus influenzae Nobel Laureate & Emeritus type b, everywhere the vaccine is used. Before the vaccine became available, 20,000 cases of the Professor, Biochemistry, University disease were reported and nearly 600 died each year in the United States. of Washington Francis T. Fitzpatrick, MD For more information about vaccines and immunization, we recommend that you talk to your physician, Pediatrician, Pennsylvania nurse or local health agency. This message is brought to you by the Albert B. Sabin Vaccine Institute, Inc., Ed Friedmann, PA-c a public 501(c)(3) charitable organization, www.sabin.org. President, American Academy of Physician Assistants Timothy A. Gardner, MD US Army Medical Department As of June 30, 2002, the following medical and public health leaders Activity, Fort Riley, Kansas William G. Gardner, MD have signed the Open Statement on Vaccines. Chairman, Dept. of Internal Medicine, Northeastern Ohio Mohammad Akhter, MD, MPH Mark P. Becker, PhD Walter E. Brandt Universities College of Medicine Executive Director Dean, School of Public Health Senior Program Officer, Malaria Anne G. Gershon, MD American Public Health Association University of Minnesota Vaccine Initiative, Program for Professor of Pediatrics, Columbia Appropriate Technology in Health Richard D. Andersen, MD Georges Benjamin, MD University Infectious Disease Consultant President, Association of State and Howard S. Britt, MD David Gilbert, MD Children’s Hospitals and Clinics Territory Health Officials Pediatrician, New Jersey President, Infectious Diseases Carol J. Baker, MD J. Michael Bishop, MD Betty Bumpers Society of America Chair, Infectious Disease Chancellor, University of Co-founder, Allan L. Goldstein, PhD Department, Baylor College of California, San Francisco Joseph A. Califano, Jr. Professor & Chair Biochemistry & Medicine Gunter Blobel President, National Center on Molecular Biology, The George Steve Barbour, MD Professor, Cell Biology and Nobel Addiction and Substance Abuse Washington University Pediatric Infectious Disease Laureate John Clymer Kathy Gray Specialist, Phoenix Children’s President, Partnership for Infection Control Practitioner, Hospital Barry R. Bloom, PhD Prevention Children’s Hospitals and Clinics, St. Kenneth Bart, MD, MPH, Dean, School of Public Health Louis Z. Cooper, MD Paul, Minnesota MSHMP Harvard University President, American Academy of Thomas P. Green, MD Director, Graduate School of Public Pediatrics Chairman of Pediatrics, Feinberg Health, San Diego State University School of Medicine, Northwestern University dedicated to disease prevention www.sabin.org 9

Neal Halsey, MD Max Michael, MD William L. Roper, MD, PhD Allen C. Steere, MD Director, Institute for Vaccine Dean, School of Public Health Dean, School of Public Health Zucker Professor of Medicine Safety, Bloomberg School of Public University of Alabama The University of North Carolina Tufts University School of Health, Johns Hopkins University Lewis A. Miller at Chapel Hill Medicine Scott Halstead, MD Chairman, Intermedica, Inc. Isadore Rosenfeld, MD Thomas E. Stenvig Adjunct Professor, Uniformed Edward Miller, MD Ida and Theo Rossi Distinguished Associate Professor, College of Services University of the Health Dean/ CEO, School of Medicine Professor of Clinical Medicine Nursing Sciences Johns Hopkins University Weill Medical College, Cornell Univ South Dakota State University Peter Holbrook, MD Thomas L. Milne Allan Rosenfield, MD, FACOG Linda Stierle, MSN, RN, CNAA Chief Medical Officer Executive Director, National Assoc. Dean, Mailman School of Public CEO, American Nurses Association Children’s National Medical Center of County & City Health Officials Health, Columbia University Patricia Stinchfield, NP Peter Hotez, MD, PhD John Modlin, MD Linda Rosenstock, MD, MPH Director, Nurse Practitioner Chair, Department of Microbiology Chair, Advisory Committee on Dean, School of Public Health, Children’s Hospitals and Clinics & Tropical Medicine, The George Immunization Practices, Centers UCLA Ciro V. Sumaya, MD, MPHTM Washington University for Disease Control and Prevention Philip K. Russell, MD Dean, School of Rural Public Health Michelle Hulse, MD Jean Molleston, MD Special Advisor on Vaccine Texas A&M University System Children’s Hospitals and Clinics, St. Clinical Associate Professor of Production & Development, Office Health Science Center Paul, Minnesota Pediatrics, Indiana University of Public Health Preparedness, U.S. Eve H. Switzer, MD Patricia Johnston, MD School of Medicine Department of Health and Human Pediatrician Services Dean, School of Public Health David A. Neumann, PhD Northwest Pediatrics Loma Linda University Director, National Partnership for Heloisa Sabin E. Donnall Thomas M. Douglas Jones, Jr., MD Immunization Co-founder, Sabin Vaccine Institute Nobel Laureate Professor and Chair, University of Jerald Newberry David Satcher Fred Hutchinson Cancer Research Colorado Health Sciences Center Director, Health Information Former Surgeon General Center Warren A. Jones, MD Network, National Education Steven E. Schutzer, MD University of Washington President, American Academy of Association Department of Medicine, Patricia Thomas Family Physicians Paul A. Offit, MD University of Medicine and Author Samuel L. Katz, MD Chief, Section of Infectious Dentistry of New Jersey Research Fellow, Sabin Vaccine Wilbert C. Davison Professor of Diseases Richard S. Schweiker Institute Pediatrics, Duke University The Children’s Hospital of Former Secretary William True, PhD Patrick W. Kelley, MD, DrPH Philadelphia Department of Health and Human Interim Dean, School of Public Director, DoD Global Emerging Michael Osterholm, PhD, MPH Services Health Infections System, Walter Reed Director, Center for Disease Donna Shalala St. Louis University Army Institute of Research Research & Policy, University of Former Secretary Jeffrey P. Utz, MD C. Everett Koop, MD, ScD Minnesota Department of Health and Human Pediatrician U.S. Surgeon General (1981-1989) Jo Ann Pacis, MS, RN, PNP-C Services Patricia Wahl Koop Institute, Dartmouth College Clinical Nurse Specialist/ARNP Philip Sharp Dean, School of Public Health Mary Beth Koslap-Petraco, NP Lee Memorial Health System Nobel Laureate and Professor University of Washington Immunization Special Interest Michael D. Pappas, MD Cancer Research Center, MIT Peter N. Wenger, MD Group Chair, National Association President, Children’s Intensive Donald Shepard, PhD Medical Director, Project Vaccinate of Pediatric Nurse Associates and Caring Professor and Head, Cost- University of Medicine and Practitioners Trish Parnell Effectiveness Group, Brandeis Dentistry of New Jersey Peter Levin Executive Director, PKIDS University Deborah Wexler, MD Dean, School of Public Health (Parents of Kids with Infectious H.R. Shepherd Executive Director University of Albany Diseases) Chairman, Sabin Vaccine Institute Immunization Action Coalition/ Myron M. Levine, MD, DTPH Amy Pisani Stanford T. Shulman, MD Hepatitis B Coalition Professor and Director Executive Director, Every Child By Chief, Infectious Diseases Nancy Woods, PhD University of Maryland School of Two Children’s Memorial Hospital, Dean and Professor, School of Medicine Gregory Poland, MD Chicago Nursing Bente E. Lundh, MD, FAAP President, International Society for Alfred Sommer, MD, MHS University of Washington Pediatrician, King Edward Vaccines Dean, School of Public Health Clifford Wu, MD, FAAP Memorial Hospital, Member of Kenneth W. Purdy, MD Johns Hopkins Bloomberg Pediatrician Bermuda Advisory Committee on Fellow, Pediatric Infectious Diseases Richard Southby, PhD New Ulm Medical Center Immunization Practices Harbor-UCLA Medical Center Interim Dean, School of Public Charles S. Mahan, MD Peter Rappo, MD Health/Health Services Dean, College of Public Health Vice President, Pediatrics, The George Washington University University of South Florida Beansprout Networks Edgar K. Marcuse, MD, MPH Michelle Ratau, MD Professor of Pediatrics, Associate Research Fellow, Urban Community Medical Director, Children’s Pediatrics For an updated list of signatories in this ongoing campaign Hospital & Regional Medical New York Presbyterian Hospital please visit www.sabin.org. There you will find your state’s Center, University of Washington Judy Robinson, PhD, RN, PNP immunization requirements and other helpful information William J. Martone, MD Executive Director Senior Executive Director National Association of School about vaccines and their effectiveness in preventing and Nat’l. Fdn. for Infectious Diseases Nurses stopping the spread of infectious diseases. Robert F. Meenan, MD, MPH, MBA Dean, School of Public Health Boston University 10 SUMMER 2002 SABIN VACCINE REPORT Exploring New Vaccine Development man mucosal surfaces. Various other adjuvants besides cholera toxin and E —by Gregory Poland (continued from page 7) coli enterotoxin (including bacterial and selectively destroy the insulin secret- likely to be the only practical means of ADP-ribosylating exotoxins, interleukin ing cells. One strategy for vaccine de- protection. 29 30 Second generation vac- -1b fragment, interleukin 2, and tumour velopment is to reduce the pathological cines against anthrax, smallpox, and necrosis factor -a) have also been lymphocytic infiltration by tolerisation. 15 are being developed, and vac- shown to produce an immune response 16 24 Tolerisation involves the adminis- cines against other agents of bioterrorism after topical application.32 tration of small amounts of the same such as the haemorrhagic fever viruses antigens that are the target of the aber- and others are also in development. Transgenic edible plants to deliver vac- rant immune response, which, in the ab- However, major obstacles in producing cines. The development of plants capable sence of cytokine costimulation, fuels the such vaccines for public use include the of expressing vaccine antigens is a novel activation of T cells, which reduce in- need for a financially viable market, the and promising strategy (fig 2). Such ge- flammation. impossibility of conducting human effi- netically engineered plants would pro- In disorders such as Alzheimer’s dis- cacy trials, the intangible risk:benefit duce vaccine antigens in their edible ease, it may be possible to target the ratio at the public health level, and gov- parts and would, like amyloid protein that is responsible for ernments’ reluctance to face the reality preparations, contain no genes capable the neurodegenerative plaques observed of bioterrorism. of replicating a whole infectious organ- in this disorder. In murine models vac- ism.33 Because food plants can be re- cines have been shown to reduce and New vaccine delivery technology generated rapidly, it may be possible that prevent plaque formation, with some crops containing vaccine antigens could improvement in cognitive function.25 Virtually all recommended immunisations be produced indefinitely and on a local Other examples of potential vaccine de- require parenteral administration, and basis. Potato and tomato plants have velopment include vaccines to prevent many require a series of injections. To synthesised antigens from Norwalk vi- cocaine and nicotine addiction. With the be effective, vaccines for some diseases rus, enterotoxigenic E coli, Vibrio use of immunopharmacotherapy, anti- will need to enhance mucosal immunity cholerae, and hepatitis B virus. A re- bodies can be designed to neutralise a as well as systemic immunity. For these cently completed human study has drug rather than target the receptors in reasons, new vaccine delivery methods, shownthat a recombinant bacterial anti- the brain. Efforts are also being made to specifically alternatives to injections, are gen, subunit B of heat labileenterotoxin, develop vaccines against atherosclero- being sought. Topically applied (trans- produced in a potato and eaten resulted sis and to prevent conception.26-28 cutaneous) vaccines, transgenic edible in production of both serum antibodies plants that contain genes for human vac- (IgG and IgA) and mucosal antibodies 34 Vaccines against biological weapons cine antigens, and controlled delivery (sIgA) to the antigen. Other plants,

of mass destruction depot systems with vaccine antigens en- such as bananas, and other vaccine an- capsulated in biodegradable polymers tigens, including tetanus and diphtheria Interest has increased in biological ,may be included in futurestud- weapons of mass destruction as terror- are possibilities currently under study. ies. ists look for methods with which to in- Such new delivery methods could de- flict harm on the greatest number of crease reliance on repeated injections, Controlled delivery depot systems. The use people, with the lowest possible cost and the need for trained healthcare work- of controlled delivery of vaccine antigen, technology needs, while creating mass ers, and perhaps the need for a stringent or depot vaccine technology, reduces the panic. While vaccines have been li- cold chain for . number of parenteral injections while censed against smallpox, plague, anthrax, Transcutaneous immunisationimmunisation. Animal potentially mimicking natural infection. and others, only limited amounts of an- studies have shown the production of Various vaccine antigens have been en- thrax vaccine are being produced in the both systemic and mucosal antibodies capsulated in microspheres composed of United States for specific risk groups. after topical vaccine application. Agents biodegradable polymers such as poly Limited and ageing stockpiles of small- such as cholera toxin and the heat labile (lactic/glycolic) acid (PLGA), which can pox and plague vaccine are available but enterotoxin of Escherichia coli, in com- be targeted to various cells in the im- are insufficient for large numbers of bination with a vaccine antigen such as mune system or can form a depot at the people. tetanus , act as an adjuvant and injection site, allowing slow release of the Because of the ability of biological produce protective antibodies after be- antigen over time.35 The release profile weapons to infect and kill large num- ing applied to the skin of animals.31 Non- of vaccine antigen depends on the par- bers of people, and the risk of person- toxic mutants or subunits of cholera toxin ticle size of the delivery vehicle, and a to-person transmission, vaccines are and E coli enterotoxin would be needed, however, for any application on to hu- Continued on page 11 dedicated to disease prevention www.sabin.org 11

nation vaccines, vectored vaccines, and Continued from page 10 vaccines administered in a parenteral Additional educational

combination of large and small depot fashion. The more distant poten- resources ♦ microspheres can create a pattern that tial for person-specific vaccines based Centers for Disease mimicsthe antigen concentration profile on individual genotyping (vaccines Control and Prevention, www.cdc.gov in conventional immunisation,combining against a specific malignancy in a spe- ♦ World Health Organization, both primary and booster injections. A cific individual) will also raise serious www.who.int/home-page recent study in animals found that en- concerns. Nonethe less, the prospect of ♦ Merck Vaccines, capsulated tetanus toxoid or both preventing and treating many seri- www.merckvaccines.com Haemophilus influenzae type b ousdiseases by the use of vaccines por- ♦ National Vaccine polysaccharide elicited high antibody lev- tends an exciting era in publichealth and Information Center, 36 els that persisted for months. vaccinology. www.909shot.com ♦ DNAvaccine.com, Acknowledgments. We thank Kim Zabel for her Conclusions. The future of vaccinology www.dnavaccine.com/) a excellent editorial assistance in the development of provides tremendous promise for con- this review. DM’s current address is Pediatric Infec- global platform for vaccine trolling diseases. Vaccines will be deliv- tious Diseases, Medical College of Georgia, Augusta, research GA, USA. ered orally, by nasal spray, or ♦ Food and Drug Footnotes. Funding: GAP and this work was sup- Administration, www.fda.gov/ transcutaneously by a minimally trained ported in part by a grant from the Centers for Disease default.htm layperson and in a manner that does not Control and Prevention (AVA 001) and grants from the National Institutes of Health (AI 33144 and AI 48793). ♦ National Foundation for require expensive equipment. However, Competing interests: None declared Infectious Diseases, despite rapid advances in the develop- References www.nfid.org ment of new vaccines, concerns about 1. Centers for Disease Control. Ten great public health ♦ American Society for achievements--United States, 1900-1999. MMWR Morb vaccine safety and a rise in anti-vac- Mortal Wkly Rep 1999; 48(12): 241-243[Medline]. Microbiology, www.asm.org cine sentiment adversely affect 2. Poland GA. Current paradoxes and changing para- ♦ Infectious Diseases Society digms in vaccinology. Vaccine 1999; 17: 1605- immunisation coverage, the willingness 1611[Medline]. of America, www.idsociety.org of manufacturers to develop new vac- 3. Dhiman N, Bonilla R, O’Kane D, Poland GA. Gene expression microarrays: a 21st century tool for di- cines, and the willingness of individuals rected vaccine design. Vaccine 2001; 20: 22- 10. YH, Chiang BL, Lee YL, Chi WK, Lin WC, Chen 37 30[Medline]. YT, et al. Development of Th1 and Th2 populations and and healthcare workers to use them. 4. Poland GA, Ovsyannikova IG, Johnson KL, Naylor 38 the nature of immune responses to hepatitis B virus As advanced vaccines and vaccine S. The role of mass spectrometry in vaccine develop- DNA vaccines can be modulated by codelivery of ment. Vaccine 2001; 19: 2692-2700[Medline]. various cytokine genes. J Immunol 1998; 160: 1320- technologies become available, massive 5. Plotkin SA. Vaccines in the 21st century. Infect Dis 1329[Abstract/Full Text]. public educationefforts will be required Clin North Am 2001; 15: 307-327[Medline]. 11. Moingeon P. Cancer vaccines. Vaccine 2001; 19: to alleviate these concerns. This is par- 6. Poland GA, Rottinghaus ST, Jacobson RM, Roy 1305-1326[Medline]. M. A phase 1C study of a DNA in 12. Belshe RB, Mendelman PM, Treanor J, King J, ticularly true for DNA vaccines, combi- healthy patients nonresponsive to licensed hepatitis B Gruber WC, Piedra P, et al. The efficacy of live attenu- vaccines: preliminary results [abstract]. The fourth an- ated, cold-adapted, trivalent, intranasal influenza virus nual conference on vaccine research, Arlington, VA, vaccine in children. N Engl J Med 1998; 338: 1405- April 23-25 2001;S37:57 (www.nfid.org/conferences/ 1412[Abstract/Full Text]. vaccine01/abstracts/abss37-40.pdf). 13. King Jr JC, Lagos R, Bernstein DI, Piedra PA, 7. Wang R, Doolan DL, Le TP, Hedstrom RC, Coonan Kotloff K, Bryant M, et al. Safety and immunogenicity KM, Charoenvit Y, et al. Induction of antigen-specific of low and high doses of trivalent live cold-adapted cytotoxic T lymphocytes in humans by a malaria DNA influenza vaccine administered intranasally as drops vaccine. Science 1998; 282: 476-480[Abstract/Full or spray to healthy children. J Infect Dis 1998; 177: Text]. 1394-1397[Medline]. 8. Oka Y, Fazle Akbar SM, Horiike N, Joko K, Onji M. 14. Nichol KL, Mendelman PM, Mallon KP, Jackson LA, Mechanism and therapeutic potential of DNA-based Gorse GJ, Belshe RB, et al. Effectiveness of live, immunization against the envelope proteins of hepati- attenuated intranasal influenza virus vaccine in healthy, tis B virus in normal and transgenic mice. Immunology working adults: a randomized controlled trial. JAMA 1999; 2001; 103: 90-97[Medline]. 282: 137-144[Medline]. 9. Mancini M, Hadchouel M, Davis HL, Whalen RG, 15. Coon B, An LL, Whitton JL, von Herrath MG. DNA Tiollais P, Michel ML. DNA-mediated immunization in a immunization to prevent autoimmune diabetes. J Clin transgenic mouse model of the hepatitis B surface Invest 1999; 104: 189-194[Abstract/Full Text]. antigen chronic carrier state. Proc Natl Acad Sci USA 16. Von Herrath MG, Whitton JL. DNA vaccination to 1996; 93: 12496-12501[Abstract/Full Text]. treat autoimmune diabetes. Ann Med 2000; 32: 285- 292[Medline]. 17. McHugh RS, Nagarajan S, Wang YC, Sell KW, Fig 2. Principle of delivering vaccines Selvaraj P. Protein transfer of glycosyl- in edible plants. A gene from a human phosphatidylinositol-B7-1 into tumor cell membranes: pathogen is inserted into a bacterium a novel approach to tumor immunotherapy. Cancer Res 1999; 59: 2433-2437[Abstract/Full Text]. that infects plants (A). The bacterium 18. Poloso NJ, Nagarajan S, Bumgarner GW, Selvaraj then infects cultured leaf segments P. Development of therapeutic vaccines by direct of the selected food plant (B), which modification of cell membranes from surgically re- sprout into whole plants containing the moved human tumor tissue with immunostimulatory molecules. Vaccine 2001; 19: 2029-2038[Medline]. human pathogen gene (C). Once the 19. Tartaglia J, Bonnet M, Berinstein N, Barber B, Klein plant is eaten, it triggers an immune M, Moingeon P. Therapeutic vaccines against mela- response to the pathogen Continued on page 16 12 SUMMER 2002 SABIN VACCINE REPORT Developer of Rubella Vaccine, Stanley A. Plotkin, Receives Sabin Gold Medal Honoree Acclaimed as “Maverick” in Vaccine Development Stanley A. Plotkin, MD, best known H.R. Shepherd, for developing the rubella, or German chairman of the measles, vaccine, received the Sabin Sabin Vaccine Insti- Gold Medal on May 7, 2001 in Baltimore tute, “He epito- during the 5th Annual Conference on mizes dedication to Vaccine Research of the National Foun- conquering disease dation for Infectious Diseases. He is with vaccines and the tenth recipient of the Medal, pre- immunization, the sented annually to a scientist recognized same passion by for exemplary leadership in the field of which vaccinology and disease prevention. lived.” “Plotkin joins a highly distinguished Dr. Plotkin is a Those gathered for the 2002 Sabin Gold Medal Ceremony included, from left, Maurice group who would in any endeavor be medical and scien- Hilleman, PhD, DSc (1997 Honoree); Myron Levine, MD, DTPH (1998 Honoree); considered peers, but in the field of vac- tific advisor to Stanley Plotkin, MD (2002 Honoree); Peter Hotez, MD, PhD, Ciro de Quadros, MD, MPH (2000 Honoree); and Philip Russell, MD (1999 Honoree). cine development and application must Aventis Pasteur, also be described as mavericks,” and emeritus professor at the Univer- of other vaccines. He continues to de- Michael Katz, MD, senior vice president sity of Pennsylvania, where he served vote efforts to the development of a cy- for research, March of Dimes Birth as associate chairman of the Depart- tomegalovirus vaccine and has collabo- Defects Foundation, affirmed to an au- ment of Pediatrics. He is known as the rated on a and two dience of over 300 scientists present at “founding father” of the Pediatric Infec- rotavirus vaccines. These accomplish- the ceremony. tious Diseases Society. Dr. Plotkin de- ments have resulted in nearly 600 origi- “Stanley Plotkin is an extraordinary veloped the rubella vaccine now in use, nal publications and four editions of the figure in the field of vaccinology,” said and has worked extensively on a range Vaccines, of which he is co-editor.

The End of Polio: A Global Effort to End a Disease Photography Publisher Aperture Opens Exhibit of Sebastião Salgado Photos Photography publisher, Aperture, Salgado, and was held at Aperture’s Bur- ravages of the disease on children to the hosted an exhibition this summer titled, den Gallery in New York. Following a heroic efforts to deliver vaccine in con- “The End Of Polio: A Global Effort to showing in Berlin through September 25, flict-ridden countries. End a Disease.” The exhibit featured it will return by the year end to the To document the campaign, United the work of photojournalist Sebastião Washington, D.C. area and will visit Nations Children’s Fund (UNICEF) California and Texas in 2003. Special Representative Salgado worked “The story told in these images is very with the four Global Polio Eradication moving,” said Heloisa Sabin, widow of Initiative lead agencies: the World Health Albert B. Sabin, developer of the oral Organization (WHO), Rotary Interna- . “This exhibit educates tional, the U.S. Centers for Disease those who might not remember how Control and Prevention (CDC) and devastating the polio epidemic was and UNICEF. In 2001, Salgado journeyed how great has been the dedication of to the Democratic Republic of Congo, health care workers and the volunteers India, Pakistan, Somalia and southern of WHO, Rotary International, Sudan to witness and document efforts In Somalia, armed guards accompany health workers UNICEF, and CDC.” Mrs. Sabin is co- to eradicate polio from some of the most during the March 2001 round of National founder of the Sabin Vaccine Institute challenging and remote places on earth. Immunization Days aimed at vaccinating all children and a trustee of the Institute. “The End of Polio” breaks with tradi- under the age of five. To reach children in conflict The photographic exhibition is the first tional photography exhibition formats in zones, international partners have negotiated depicting the epic story behind the larg- that Salgado’s imagery goes beyond pro- complex logistical arrangements, including est public health initiative in history— moting public awareness. It points to a temporary cease-fires between warring factions the bid to eradicate polio globally by solution and encourages participation by called ‘Days of Tranquillity’. These efforts must continue, as many of the remaining 10 polio- 2005. Salgado’s images tell the polio demonstrating that the eradication of

2001 Sebastião Salgado/Amazonas Images/Contact Press Images endemic countries are affected by conflict. eradication story by both depicting the polio is within grasp.

 dedicated to disease prevention www.sabin.org 13 SVI Convenes Scientific Meeting on Bioterrorism Facing the Challenge: Disease Prevention in a Time of Crisis

The Sabin Vaccine Institute presented on “Solving the Problem Through Vac- a one-day scientific colloquium May 30 cines,” with speakers Samuel L. Katz, on the theme, Facing the Challenge: MD, Duke University Medical Center; Disease Prevention in a Time of Cri- , MD, Children’s Hospital of sis, held at the New York Academy of Sciences in New York City. Prominent guest speakers examined the nation’s vulnerability and public health response to bioterrorism and the role of vaccines in the nation’s defense. The meeting was funded by GlaxoSmithKline and organized by Pe- ter J. Hotez, MD, PhD, chairman, De- partment of Microbiology and Tropical Medicine, The George Washington Uni- versity (GW) Medical Center, and chair of the Sabin Vaccine Institute Scientific Scientific Colloquium presenters and organizers gather at the New York Academy of Sciences. Front row, Advisory Council, and Allan L. from left, Margaret Hamburg, MD; Peter Hotez, MD, PhD; Tee Guidotti, MD, MPH, Tom Zink, MD; Sam Katz, Goldstein, PhD, chair, Department of MD; and Tom Frieden, MD. Back row, from left, Philip Russell, MD; John Robbins, MD; John Woodall, Biochemistry and Molecular Biology, PhD; Allan Goldstein, PhD, and Paul Offit, MD. GW, and Sabin Vaccine Institute trustee. Hotez moderated the morning session Tee L. Guidotti, MD MPH, GW. Tho- Philadelphia; and John B. Robbins, MD, on “How Vulnerable Are We? Why?” mas Frieden, MD, New York City pub- National Institute of Child Health and The guest speaker line up included Mar- lic health commissioner, provided the lun- Human Development, National Institutes garet Hamburg, MD, Nuclear Threat Ini- cheon keynote message. In the after- of Health. tiative; John P. Woodall, PhD, Federal noon, Major General Philip K. Russell, Hotez invited the group to address University of Rio de Janeiro, Brazil; and MD (USA Ret.), moderated a session “one of our nation’s great challenges, namely, how to rebuild our public health infrastructure to combat new enemies Patricia Thomas Welcomed by SVI and GW armed with bioweapons.” Vaccine Author of Big Shot: Passion, Politics, and the Struggle for an AIDS shortages were exemplified by the lack Vaccine Discusses Her Book at Special Evening With the Author of a ready-to-use stockpile of anthrax vaccine and want of an adequate stock- pile of . He added that “equally troubling is the new realization that our nation’s vaccine supply for childhood immunizations, including teta- nus, is in danger.” The group was called upon to look at the problems facing our national public health infrastructure in a new light.

“Our nation’s vaccine supply for childhood Patricia Thomas, author of Big Shot: Passion, Politics, and the Struggle for an AIDS Vaccine, is welcomed by Sabin Vaccine Institute Trustee Allan Goldstein, PhD, chair of Biochemistry and Mo- immunizations, including lecular Biology at The George Washington University. Thomas, a Sabin fellow, read passages from her tetanus, is in danger . . .” book that chronicles the search for an AIDS vaccine. —Hotez 14 SUMMER 2002 SABIN VACCINE REPORT Polio Vaccine Trials and a Little-known Chapter in U.S.-Soviet Cold War Diplomacy Lifting the Iron Curtain Chronicles Vaccine Scientists’ Collaboration During Icy Period Between U.S. and Soviets

A Russian virologist writes of an his- cal scientists roughly coincided with the SABIN VACCINE INSTITUTE toric period of bilateral collaboration at Sputnik launch and is a remarkable, but the height of the Cold War in a new re- little known chapter in the history of mod- PUBLICATION lease from the Sabin Vaccine Institute, ern vaccine science. Lifting the Iron Curtain. Alexander The live oral polio vaccine pioneered About The Author Anatolievich Smorodintsev, MD, PhD, by the late Dr. Albert B. Sabin in his Alexander A. Smorodintsev, M.D., was a member of his father’s research Cincinnati Children’s Hospital laboratory Ph.D., was born in 1929 in Leningrad team and eye-witness to the fortunate was licensed in the U.S. only after it (now St. Petersburg), Russia, son of the partnership between his father, Anatoli was first tested in thousands of Soviet late Anatoli A. Smorodintsev. He ob- Smorodintsev, MD, Mikhail Petrovich children. The successful collaboration tained his medical degree from the Medi- Chumakov, MD, and the U.S. oral polio is a testament to the power of vaccines cal University of Leningrad and his vaccine developer Dr. Albert B. Sabin. to break down national, political, and Ph.D. in virology, immunology and The scientists from ideological barriers. It is vaccinology. During the 1950s Dr. Cold War adversary an impressive example of Smorodintsev worked closely with Dr. nations faced off what we sometimes term Albert B. Sabin on the development of against a common “vaccine diplomacy.” live attenuated oral polio vaccine (OPV), enemy, poliomyelitis, Smorodintsev’s account and his daughter was one of the first which at the time is a powerful reminder of children to be immunized with the ex- threatened the youth how vaccines can serve perimental vaccine. He later served as of both countries as agents of conflict reso- Chief of the Laboratory at the State In- with grave illness and lution. It provides a les- fluenza Research Institute and at the crippling long-term son that is still relevant to Pasteur Institute in St. Petersburg. Be- effects. civil conflicts in Africa and tween 1968 and 1976, he was an offi- Very few of us are Central Asia, and possibly cial coordinator of Soviet-American col- aware that the live even to international con- laborative work on influenza, and from oral polio vaccine that flicts among the major 1976 to 1985 coordinator of Russian- we received as chil- superpowers. Finnish collaborative studies on human dren was developed Also included in this interferon. He has published more then only with the help of new book is a reprinting 200 scientific papers and made many Soviet virologists in the 1950s. The of Saul Benison’s “International Medi- contributions to the cultivation, pathogen- events Smorodintsev describes unfold cal Cooperation: Dr. Albert Sabin, Live esis, and vaccinology of respiratory vi- over a period of three to four years at Poliovirus Vaccine, and the Soviets,” ruses such as measles, mumps, and ru- the very height of US-Soviet Cold War from the Bulletin of the History of bella. tensions. This unprecedented coopera- Medicine, originally published in 1982 tion between American and Soviet medi- by The Johns Hopkins University Press. Book Ordering Information Vaccine Supply Needs a Shot in the Arm The new release, Lifting the Iron continued from page 5 Curtain, is available from the Sabin fect of preventing disease, vaccines health officials, policymakers, physi- Vaccine Institute for US $15 (add $8 have tended to be underfunded and cians, and parents alike. Recent meet- for international orders). Those underappreciated. This neglect, some ings of the National Vaccine Advisory wanting to purchase the book may claim, is manifested in the decline of Committee as well as others have dis- send a check or money order to Albert the vaccine industry, its consolidation cussed several options for shoring up the into a handful of firms, and the break- supply, including rotating stockpiles, na- B. Sabin Vaccine Institute, 58 Pine down of the entire system of develop- tional immunization awareness cam- Street, New Canaan, CT 06840, or call ment, manufacture, delivery, and moni- paigns, and other initiatives aimed at ad- (203) 972-7907 for credit card toring. The recent shortages, results dressing the current shortages and pre- purchases. of an unstable supply, concern public venting them in the future. dedicated to disease prevention www.sabin.org 15 SVI Honors Pharmaceutical CEO and U.S. Diplomat at New York City Benefit Dinner GlaxoSmithKline’s Jean-Pierre Garnier, PhD, and The Honorable Richard C. Holbrooke Recognized for Humanitarianism and Leadership The Sabin Vaccine Institute presented has been an advocate for humanitarian tion as an global priority and to rede- its two highest non-science awards on efforts through which GlaxoSmithKline fine the great scourge of HIV/AIDS May 30 to Jean-Pierre Garnier, PhD, has engaged in international coopera- as a matter of global security. ” Chairman and Chief Executive Officer tion and independent disease preven- Heloisa Sabin, widow of the late of GlaxoSmithKline, and The Honor- tion efforts to combat preventable Albert B. Sabin, introduced the Hu- able Richard C. Holbrooke, Former childhood diseases, the great HIV/ manitarian Award recipient; William U.S. Permanent Representative to the AIDS epidemic, and disfigurement of Haseltine, PhD, chairman of the board United Nations. Garnier received Lymphatic Filariasis. Richard of Directors and CEO of Human Ge- Sabin’s Humanitarian Award and Holbrooke has drawn upon his interna- nome Sciences, Inc., introduced the Holbrooke received the Institute’s Life- tional profile to elevate disease preven- Lifetime Achievement winner. Col- time Achievement Award leagues of the honorees at a benefit dinner at The and corporate and indi- Pierre Hotel in New York vidual supporters of the City. Sabin Vaccine Institute “We honor two individu- were represented at the als this year both of whom dinner in Garnier and are engaged strategically Holbrooke’s honor. The in the global effort to meet awards dinner is an annual the health needs of popu- benefit for the Sabin Vac- lations whose vulnerabil- cine Institute. Co-chairs ity to disease is great, but of this year’s event were whose resources are ex- Jean Stéphenne, tremely limited,” said GlaxoSmithKline H.R. Shepherd, Chairman Biologicals, and Sanford I. of the Sabin Vaccine In- Weill, Citigroup, Inc. The stitute. “Jean-Pierre Honorable Hillary Garnier’s corporate vision Pictured at the 2002 Sabin Vaccine Institute Annual Dinner are, from left, the Honorable Rodham Clinton, United and leadership has been Richard C. Holbrooke, GlaxoSmithKline CEO Jean-Pierre Garnier, PhD, and H.R. Shepherd, States Senate, was Hon- widely recognized and he Chairman of the Sabin Vaccine Institute. orary Chair.

2002 SABIN VACCINE INSTITUTE’S LIFETIME ACHIEVEMENT AWARD HONOREE Richard C. Holbrooke served as the U.S. Ambassador to the United Nations and member of President Clinton’s cabinet from 1999 to 2001. He played a central role in the development of U.S. policy toward the United Nations, the Balkans, Africa, Asia, the Middle East and humanitarian crisis issues such as AIDS. As Assistant Secretary of State for Europe from 1994 to 1996, Holbrooke was chief architect of the momentous 1995 Dayton peace agreement that ended the war in Bosnia. He previously served as U.S. Ambassador to Germany and as Assistant Secretary of State for East Asian and Pacific Affairs. There, he was in charge of U.S. relations with China when Sino-American relations were normalized in 1978. He is president and CEO of the Global Business Council, the business alliance against HIV/AIDS and is currently Vice Chairman of Perseus, a leading private equity firm. 2002 SABIN VACCINE INSTITUTE’S HUMANITARIAN AWARD HONOREE Jean-Pierre Garnier is chief executive officer of GlaxoSmithKline. He assumed this role in December 2000 with the merger of SmithKline Beecham and Glaxo Wellcome. Dr. Garnier joined SmithKline Beecham in 1990 as president of its pharmaceutical business in North America and served as chairman, Pharmaceuticals from 1994 until his appointment as chief operating officer in 1995. He was elected to the company’s Board of Directors in 1992. He became chief executive officer in April 2000. Prior to SmithKline Beecham, Dr Garnier served as President of Schering-Plough’s US business. Dr Garnier serves on the boards of the United Technologies Corporation and the Eisenhower Exchange Fellowships, Inc. In January 1997, Dr Garnier was selected by President Chirac of France to receive the Chevalier de la Légion d’Honneur. In 2001, he was named one of 50 “Stars of Europe” by BusinessWeek magazine. Dr Garnier holds a PhD in pharmacology and an MS in pharmaceutical science from the University of in France. As a Fulbright Scholar, he earned an MBA at Stanford University, California, in 1974. 16 SUMMER 2002 SABIN VACCINE REPORT

Vaccine Development SABIN Gregory Poland Explores the Latest Vaccine Science, from page 10 CALENDAR noma and colorectal cancer. Vaccine 2001; 19: 2571- SEPTEMBER 2002 23 - 25 Cold Spring Harbor, New York 2575[Medline]. 20. Kochenderfer JN, Molldrem JJ. Leukemia vaccines. 11-12 Copenhagen, Denmark 9th Anual Sabin Vaccine Colloquium: Curr Oncol Rep 2001; 3: 193-200[Medline]. Thorvald Madsen Intl. Vaccine Gobal Vaccine Shortage: The Threat 21. Knutson KL, Schiffman K, Disis ML. Immunization with a HER-2/neu helper generates Symposium: Vaccines for the 21st To Children and What To Do About It HER-2/neu CD8 T-cell immunity in cancer patients. J Century-Development and Strategies Contact: Veronica Korn Clin Invest 2001; 107: 477-484[Abstract/Full Text]. E-mail: [email protected] E-mail: [email protected] 22. Chen Y, Emtage P, Zhu Q, Foley R, Muller W, Hitt M, et al. Induction of ErbB-2/neu-specific protective and therapeutic antitumor immunity using genetically 16 - 27 Antwerp, Belgium 23 - 25 Edinburgh, Scotland, UK modified dendritic cells: enhanced efficacy by cotrans- Twenty-first European Course in DNA Vaccines 2002 - The Gene duction of gene encoding IL-12. Gene Ther 2001; 8: Tropical Vaccine Conference 316-323[Medline]. 23. Sivanandham M, Shaw P, Bernik SF, Paoletti E, Contact: Anne Marie Trooskens Contact: John Herriot Wallack MK. Colon cancer cell vaccine prepared with [email protected] [email protected] replication-deficient vaccinia viruses encoding B7.1 and interleukin-2 induce antitumor response in syngeneic 18 - 22 Hinxton, United Kingdom 24 - 27 Chicago, Illinois mice. Cancer Immunol Immunother 1998; 46: 261- th 267[Medline]. 7 Intl. Symposium on Pertussis: IDSA 2002 - 40th Annual Infectious 24. Simone EA, Wegmann DR, Eisenbarth GS. Immu- Genome, Pathogenesis, and Immunity Diseases Society of America Meeting nologic “vaccination” for the prevention of autoimmune diabetes (type 1A). Diabetes Care 1999; 22: 7-15[Ab- www.asmusa.org/mtgsrc/Pertussisg.htm Contact: Suzanne Johnson-DeLeon stract]. E-mail: [email protected] 25. Janus C, Pearson J, McLaurin J, Mathews PM, 19 - 22 Anaheim, California Jiang Y, Schmidt SD, et al. A beta peptide immuniza- 6th Annual U.S. Conference on AIDS 28 - 30 Philadelphia, Pennsylvania tion reduces behavioural impairment and plaques in a rd model of Alzheimer’s disease. Nature 2000; 408: 979- Conference Registrar: Paul Woods 3 Annual Immunization Registry 982[Medline]. [email protected] Conference 26. Naz RK, Zhu X, Kadam AL. Cloning and sequencing E-mail: [email protected] of cDNA encoding for a novel human testis-specific 30 - October 1 New York, New York contraceptive vaccinogen: role in immunocontraception. Mol Reprod Dev 2001; 60: 116-127[Medline]. Collaborative NOVEMBER 2002 27. Santhanam R, Naz RK. Novel human testis-spe- www.cancerresearch.org/cvc2002 10 - 14 Denver, Colorado cific cDNA: molecular cloning, expression and Amer. Society of Tropical Medicine& immunobiological effects of the recombinant protein. 30 - October 2 Lyon, France Mol Reprod Dev 2001; 60: 1-12[Medline]. Hygiene 51st Annual Meeting World Vaccine Congress 2002 28. Hasegawa A, Hamada Y, Shigeta M, Koyama K. E-mail: [email protected] Contraceptive potential of synthetic peptides of zona Contact: NYAS pellucida protein (ZPA). J Reprod Immunol 2002; 53: 91- 98[Medline]. E-mail: [email protected] 9 - 13 Philadelphia, Pennsylvania 29. Lillibridge SR, Bell AJ, Roman RS. Centers for American Public Health Association OCTOBER 2002 disease control and prevention bioterrorism prepared- 130th Annual Meeting: Putting the ness and response. Am J Infect Control 1999; 27: 463- 2 - 5 Charlotte, North Carolina Public Back Into Public Health 464[Medline]. The 76th Annual American School 30. Cieslak TJ, Christopher GW, Kortepeter MG, Rowe www.globalhealth.org JR, Pavlin JA, Culpepper RC, et al. Immunization Health Association Conference against potential biological warfare agents. Clin Infect Contact: Mary Bamer Ramsier 19 - 23 Santiago, Chile Dis 2000; 30: 843-850[Medline]. 31. Scharton-Kersten T, Glenn GM, Vassell R, Yu J, E-mail: [email protected] 3rd World Congress of Pediatric Walwender D, Alving CR. Principles of transcutaneous Infectious Diseases immunization using cholera toxin as an adjuvant. Vac- 13 - 15 Nice, France E-mail: [email protected] cine 1999; 17: S37-S43[Medline]. Pros and Cons in Infectious Diseases 32. Glenn GM, Scharton-Kersten T, Vassell R, Matyas GR, Alving CR. Transcutaneous immunization with bac- E-mail: [email protected] terial ADP-ribosylating exotoxins as antigens and adju- vants. Infect Immun 1999; 67: 1100-1106[Abstract/Full Text]. 33. Langridge WH. Edible vaccines. Sci Am 2000; 283: 66-71[Medline]. NON-PROFIT ORG. 34. Tacket CO, Mason HS, Losonsky G, Clements JD, U.S. POSTAGE Levine MM, Arntzen CJ. Immunogenicity in humans of a recombinant bacterial antigen delivered in a transgenic PAID potato. Nat Med 1998; 4: 607-609[Medline]. MONTROSE, PA 35. Zhao Z, Leong KW. Controlled delivery of antigens and adjuvants in vaccine development. J Pharm Sci PERMIT NO. 2 1996; 85: 1261-1270[Medline]. 58 Pine Street 36. Gupta RK, Chang AC, Siber GR. Biodegradable RETURN SERVICE REQUESTED polymer microspheres as vaccine adjuvants and de- New Canaan, CT 06840 livery systems. Dev Biol Stand 1998; 92: 63- U.S.A. 78[Medline]. 37. Poland GA, Jacobson RM. Vaccine safety: inject- ing a dose of common sense. Mayo Clin Proc 2000; 75: 135-139[Medline]. 38. Poland GA, Jacobson RM. Understanding those who do not understand: a brief review of the anti- vaccine movement. Vaccine 2001; 19: 2440- 2445[Medline].