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Poliomyelitis 1963
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· · · · · · · lie- · ··· ,· .... · . · m eca..c; Ias.·.· ,• .• .• .• .• .• .• • • .• • • llA• • • • ,,··.......... •.••.••.•.."a.t~ i . . . .. I
.. . . . · . . . . .. tj ...• •
• • • • • •
..~
·• • .• •.• •.• • .• •.• • •• •8r~. JI ..· • • • • • •••
• • • • • • .c:. ~
• • • • • • • • • • •
n March 21, HEW Secretary Anthony J. Celebrezze approved licenses fo r manufacturing two types of measles vaccine. M erck , Sharp a nd Dohme was granted a license fo r a live attenuated m easles vaccine and Chas. Pfizer and Company, Inc., received a license t o market a killed-virus vaccine. Licen sing these two fo rms of measles vaccine brings t o a fo reseeable en d a nother contest between m an and virus which has lasted for hundreds of years. T he invidious measles virus, like its many deadly brothers, is immune to ant ibiotics, too small to be caught with an ordinary microscope and controllable only by t he body's own defenses. The on ly offense against it, t herefore, is a strong defense- t o make t he body resist ant before t he virus strikes . 11easles vaccine, capable of protecting m illions of children against the und errated disease, is t he newest achievement of immunology. Known medically as rubeola a nd morbilli, measles is an acute, highly contagious viral disease, with illness generally lasting fo ur to ten days. T he incubation period, from fi rst exposure unt il onset of symptoms, is seven to 14 days. F irst symptoms include feve r , a runnin g nose, sneezing, puffy eyelids and red eyes and a harsh bronchial cough. T hese are followed wit hin 24 to 48 hours by appearance of lesions or markings (K opEk 's spots) inside t he mouth on t he cheek 's m ucous membranes. Three t o five days after the onset of symptoms, t he telltale measles rash appears- a distinctive dusky-red , blotchy skin eru ption which st arts behind the ears a nd on the fo rehead , extends t o t h e fa ce, neck and t runk and finally reaches the a rms and legs. T he measles virus seems t o be transmitted entirely fro m person t o person , proba bly by infectious droplets fro m the nose and throat . T he pa tient can infect others fro m t wo t o four days before t he rash appears until two t o five days after it appears. 11easles antibodies u sually develop about this time (about three weeks after initial contact ). One attack generally gives th e victim lifelong immunity. 11easles attacks about 95 percent of the population of the United States. It is almost inevitable in childhood ; m ost people have had measles b y age 15. Wit h births currently
O
numbering about 4,200, 000 a year (4,282,000 in 196 1), the number of measles cases probably averages about 4,000 ,000 annually. No t too lon g ago, m easles was regarded m ore as a subject fo r humor than as the scourge it really is- cartoons of spotty-faced children t ypified the casu al attitude of the public t oward the disease. Its seriousness is sti11largely unrecognized t oday. Measles is, in fact, all t oo often a killer or the cau se of mental crippling and m ore than t wice as many children die each year from measles com plications as from poliomyelitis.
a small villain M easles is so widespread that it almost certainly exist ed in a ncient t imes yet t he first account of it did not appear until t he writ ings of Rhazes in the 10th century. By the Middle Ages it was common throughout E urope and Asia and was confused wit h , or associated with , other exanthemic (eruptive) diseases such as smallpox. By t he 16th century, physici ans were different iating it from the other eruptive diseases, giving it t he Latin name morbilli. The E nglish word mesles was a corrupt ion of t he Latin miselli (from miser) b ut which referred t o t he sores of leprosy, another confusion in t he medieval mind. And alt hou gh measles was fin ally distinguished from b oth leprosy and smallpox, it cont inued t o be confused with scarlet feve r until the en d of t he 18th cent ury . Measles came to America wit h t he colonists and t here were out breaks t hroughout the 16th a nd 17t h cent uries in many parts of Spanish America. In 1785 t here was a severe epidemic in Ec uador- more t han 2,400 died at Quito. Among t he F rench and Indians, a minor epidemic was reported in 1635 and a severe one in 1687 in Quebec. Bost on was hit in 1657 and again in 1687, the latter infect ion possibly having been bro ught in from Canada. This epidemic produced the first medical document printed in t he American colonies- A B rief R ·tle to Guide the Common-P eo ple of New England H ow to Order Them selves and Theirs in the S m all-P ocks or .ilI/easles- b y Thomas Thacher in which he continued the belief t hat the t wo diseases were relat ed. New E ngland had severe epidemics from 1713 t o 171 5 with 150 deaths at Bost on . Conn ect icut had a serious epidemic in 1740 and the other colonies were stru ck at intervals. Noah Webst er reported an outbreak in Charlestown , N ort h Carolina in 1772 in which " died 800 or 900 children ." Since one attack of measles produces a permanent immunity, the sparsely populated American colonies had fairly long res pites bet ween epidemics until new birt hs had increased t he population sufficiently for another crop of su sceptibles t o become available. By the end of the colonial period, t he settled areas of America were well seeded wit h measles virus. From then on , measles followed the tide of empire westward and the pattern of epidemics spread throu gh K entucky and Ohio with the pioneers. In modern times the epidemics occur at usual intervals of three to four years, mostly in the springtime. There may be localized outbreaks in the spring of off-years. During vVorld vVar II , measles was something of a military problem , Vol. NS3, No.5, May 1963
243
particularly in countries like Iceland and Greenland where large numbers of troops were quartered upon a population highly susceptible to the virus. Similarly, the disease has been very severe in Eskimos as it reached them.
One of the first steps in preparing the live-virus measles vaccine marketed by Merck Sharp and Do h m e is removing the emb ryos from the chicken eggs. This removal is done under a sterile hood .
When the heads and feet have been removed from the embryos (above), the embryos are ground into a mince and trypsinized (below). The mince is placed in flasks and trypsin is added to break down the m ince into in dividual cells or groups of cells.
searchers Attempts to control measles date back at least to 1758 when Francis Home at Edinburgh inoculated 12 children with blood from measles victims in the hope that he could induce a mild form of the disease which would confer immunity. The full cases of measles which developed in seven of the children demonstrated the transmissibility of the disease, but offered no hope that an attenuated form could be induced in this way. Hope for the control of measles was meager until the beginning of the 20th century. In 1911 John F . Anderson and Joseph Goldberger proved that measles is caused by a filterahle yirus. In 1938 Harry Plotz published his report on the successful growing of measles virus in tissue cultures and between 19;39 and 1943 the virus was cultivated in chick embryos by Geoffrey Rake and Morris Shaffer. Attempts to create a \raccine from this attenuated strain of virus were, however, unsuccessful. Enders breakthrough The way toward development of a practical, effective measles vaccine was opened in ] 95-l by Drs. John F. Enders and Thomas C. Peebles of Harvard Medical School. These scientists succeeded in culturing measles virus from the blood and throat washings of an ll-year-old boy named David Edmonston. The virus at first could he made to grow in laboratory cultures of monkey and human kidney tissue. Its presence could be demonstrated by the pathologic changes it caused in these cells. Dr. Enders and his associates subsequently grew the Edmonston strain in 24 successive cultures of human kidney tissue and then in 28 serial cultures of human amnion. At this point they managed to adapt it to fertilized hens' eggs and finally to single-layer cultures of chick-emhryo cells in laboratory glassware . The virus grew rapidly on the chickembryo tissue cuI tures. After a number of passages in the eggs and tissue cultures, tests shov,ed the virulence of the infecting agent had been weakened. In monkeys the virus caused a mild infection that stimulated the animals to form antibodies and the monkeys subsequently resisted infection by full-strength measles virus capable of producing disease in unvaccinated animals. In addition, there was no evidence of viremia, no recognizable infection of the central nervous system and no detectable ,-irus in the upper respiratory tract. \\Then given (in 1958) t o children who had not had measles, the attenuated virus produced only a mild form of the disease with significant development of measles antibodies. Hence, the Enders group had succeeded in developin g an attenuated-virus vaccine that promised to put an end to the 200-year search. From this point, the quest for a practical vaccine branched off into a number of parallel pathways, with some interesting side excursions. For example, it was found that distemper, a serious disease of dogs, is caused by a virus closely related to the measles virus and man has been found to have circulating antibodies to the canine agent. However, attempts to immunize man against measles with canine distemper vaccine have thus far been unsuccessful. Research is continuing 011 this interesting interviral relationship. By the latter part of 1961, there were several potential measles vaccines in various stages of preparation. \\There the search for a polio vaccine had produced first a killed-virus vaccine (Salk) and then a live vaccine (Sabin), measles research resulted in the development of both killed and live vaccines simultaneously. government approval Under the ~ ational Biologics Control Act, a license for the
manufacture and interstate distribution of vaccines, serums, antitoxins and similar biological products for medical use can be issued when the manufacturer demonstrates that his product meets federal standards of safety, purity and potency. Such products are tested and evaluated by the division of biologics standards of the National Institutes of Health, research arm of the Public Health Service. Over the last several years, the vaccines have been successfully tested both in this country and abroad. Nearly 50,000 children in the United States alone have received these vaccines in field trials. Secretary Celebrezze characterized the field trials as "a long and painstaking evaluation" and saidThis was made possible by the co-operative efforts of scientists-both in and out of government-by physicians, the pharmaceutical industry and thous ands of unselfish and courageous parent s who have permitted their children to participate in the field trials. This splendid teamwork between science, government, industry and the general public has scored a great victory for better child health which will be hailed in all countrie'5 and by all people .
live-virus vaccine Lyovac Rubeovax (Merck Sharp and Dohme) is a live attenuated measles vaccine, developed for single-dose immunization against the disease. The use of Rubeovax without the co-administration of immune serum globulin (human) standardized for measles antibody content may be accompanied by rash and fever, both of which may be severe. Therefore, Merck Sharp and Dohme has introduced Gammagee, an immune serum globulin (human) that has been standardized for its concentration of measles ~mtibodies for use in conjunction with Rubeovax, t o modif," the mild measles infection induced by the vaccine . Each immunization of Lyovac Rubeoyax is supplied in two packages- a 0.5 cc vial containing one dose of lyophilized vaccine and an accompanying, separate package containing a 0.7 cc ampul of sterile diluent and a plastic disposable syringe with needle for reconstitution and injection of the vaccine. Because the lyophilized vaccine must be kept at temperatures near freezing (no higher than five degrees C. or 41 degrees F.) while the diluent must not be frozen (to avoid breakage of the ampul), a special shipping container was developed by l\1"erck Sharp and Dohme to accommodate both at the proper temperatures. This container, of molded polystyrene , accommodates ten complete immunizations. It is divided into two compartments insulated from each other. One contains the vaccine and dry ice which will keep it at proper temperature for about 54 hours; the other contains the diluent and syringe and also space for Gammagee. The reconstituted Lyovac Rubeovax live attenuated measles vaccine , in a dose of 0.5 cc, is injected subcutaneously into the upper arm. Injection of the vaccine into the buttock has given poor results. Each 0.5 cc dose of reconstituted Rubeovax contains no less than 1,000 TCID 50 of measles virus vaccine expressed in terms of the assigned titer of the NIH reference measles virus. Gammagee immune serum globulin is administered in a dose of 0.01 cc per pound of body weight, injected immediately thereafter into the deltoid muscle of the opposite arm. Neither Gammagee nor Rubeovax should be injected intravenously. It is recommended that only children eight months of age and over be immunized since earlier immuni zation may not take due to maternal antibodies. Measles vaccine is contraindicated in individuals with leukemia and should be avoided in patients with active t uberculosis not yet under treatment. There is no indication for its administration to pregnant women in the hope of averting congenital anomalies. Any febrile respiratory illness or other active infection is reason for delaying use of the vaccine unless, in the opinion of the physician, withholding the agent entails even greater risk.
In clarifying measles vaccine, the pooled fluids are passed under pressure through filters (being adjusted by the techn icia n) which remove cellular material, then through an ice bath and then into an othe r pooling tank (foreground) to form an homogeneous vaccine .
Vials are filled with measles vaccine under sterile conditions. A measured amount of vaccine is delivered automatically through the tube for each vial. Ultraviolet light protects the operation and only one row of vials at a time is exposed for filling. When it is completed , the operator exposes an adjacent row by turning the handwheel. The vialed vaccine is then quick-frozen .
A small number of persons are extremely allergic to egg proteins and may show severe re actions to injections of a vaccine derived from chick embryos. Thus use of this, or any vaccine prepared from a medium containing chick protein, is absolutely contraindicated in persons with a hist ory of hypersensitivity t o egg, chicken or chicken feathers . Elective immunization should be deferred during an outbreak of poliomyelitis since there is indication it may result in localization of paralysis in the inoculated arm of those patients who may subsequently develop paralytic polio. U.S. Public Health Service Surgeon General Luther Terry Vol. NS3, No .5, May 1963
245
has endorsed the report of his ad hoc advisory committee recommending the use of the live vaccine, except under special circumst ances, because of its lon ger-las ting immunity after a single inj ection. T he live-virus vaccine does n ot require booster shot s as does t he killed vaccine. T he live-virus vaccine will reportedly prod uce ab ove 95 percen t protection .
kill ed vaccine
To make killed vaccine large quantities of pure virus are needed and these can be grown only In living cells . Techn icians at Charles Pfizer and Company laboratories fill large flasks with nutrient med ium and livin g cells which will be grown to serve as hosts for t he measles ·virus.
Chas. Pfizer and Company placed on t he market in April an inactivated (killed) measles virus vaccine, packaged initially in 10-dose vials. It can be stored under normal refrigerati on and will n ot require the use of gamma globulin with it since it will n ot produce t he reactions associated wit h t he u se of the live-virus vaccine, but it will require t hree inj ection s a mont h apart for com plete immunity. Clinical test s indicate that measles antibodies of a pr otective level were developed in between 90 and 95 percent of t hose receivin g either the three injections of inactivat ed vaccine or t he two inj ections of inactivated followed by one injection of attenuated live vaccine. T he Pfizer vaccine has been developed fr om t he E dmonston strain of virus isolat ed by J ohn Enders an d it is being produced at Pfizer's biological product ion center in Terre Hau te, Indiana. P hilli ps R oxane has developed a live-v irus measles vaccine which is m ade by growing its virus on dog kidney tissue. Philli ps Roxane claim s t hat dog kidney tissue has been fo und to be ge nerally free of t he wi ld viruses that sometimes plague vaccine m anufacturers. Because no other commercial vaccine has ever been grown on dog kid ney t issue, t he government is requiring considerably more testing on Phillips vaccine before it will be licensed. •
......... ........ ......... pol iomyel itis- 19S3 (continu ed from page 242)
A scientist examines cells grown by tissue culture technic (above). The microscope shows cells developing normally and free of invad ing orga nisms . They will se rve as host for the virus from wh ich th e vaccine will be m ade. Living cells grow in an incubator (below) at the virus laboratories of Pfizer. All operations are carried out under the strict est cond itions of st eril ity.
important purpose- focusing public attention on the whole question of how individual and community health are maintained and protected in our society. Public relations has been defined as " good deeds properly celebrated." T he definition cert.ainly applies here. The experience with polio has inevitably led to consideration of other forms of social action against other illnesses. Last year, the Congress passed legislat.ion to combat three other diseases of childhood- whooping cough, tetanus and diphtheri a. T itled the Vaccination Assistance Act, the legislation calls for aid to t he states to undertake t he vaccination of all children un der five, inclu ding t he fo ur m illion a nnual newborns, against t hese diseases and against polio. The present Congress has before it a request for fun ds to get t.his farreachin g, long-range progra m under way. Not all details have been worked out-·for funding, for administration or for the ve ry su bstantial and sustained job of public education that will be req uired by both t he U.S. P ublic Health Service a nd t he states. It is ob vious, however , t hat t he possibilit ies inherent in t his legislation are t remendous- ·na mely, t he fmal elimin ation of all fo ur of t hese ancient enemies of childhood. To stam p t hem out we will all have to travel a long, hard road and t he struggle will , qui te possibly, be fra ught with controversy. Bu t who would say that it will not be wor th every effor t we can pu t into it? Summer , t he season of childhood's freedo m , is no longer a season of fear fo r parents . "\Vho among those who h ave known t he skirmishes a nd alarms of t he polio battle- and who hasn 't- would wish to have not endured it or to fail in cont inuing to push fo rward toward fin al victory? •
From loca l t o n ationa l lev el, group effort a m ong pharma cist s is b eing geared t oward community serv ice. This effort was dr am atically highlighted in Abington ( P ennsy lvania) M emorial H ospita l during presentation of a p oison control cabinet by M ontgomer y County Pharma ceutical Association . A 19month old ba by, a cutely p oison ed b y ingestion of m oth ba lls, was rush ed into th e em ergency wa rd during th e cer em onies and t h e cabinet was put into immediat e u se b efor e it actually b eca me t he h ospita l's p ossession . Assisting in th e su ccessful t r eatment (above left) a r e M orris George, h ospita l a dministrat or, Rich ard B . Bitner, pr esident of t h e don ating association, Alonzo Sudler, Jr. , hospita l ph ar ma cist , Irvin R eich, presentation ch airman, Philip Seltzer, president of D elawar e Vall ey E thical Pra ctices Council , J oseph T . B earwood , Jr., MD, and N urse W orthington . Wiscon sin is a n other st at e striving for complet e coverage a ga inst a ll types of accidenta l p oisoning. T ypica l of th e m an y p oison control center s which h ave b een d onat ed b y Wiscon sin pharma cist s is this on e in Shawan o Community H ospita l (top right ). Th e center was presented by (left to right) Otto R ognlien , H arvey J ewel, H enry Cook a nd J ohn G allagh er. In M organtown , West Virginia community pharmacist s spon sor ed a prom otiona l campa ign during Nationa l P oison Control Week. As p art of t h e campaign th ey set up a p oison control center in th e em ergen cy r oom of West Virginia U niversity H ospita l. Checking the list of a ntidot es (center right) a r e (left to rig ht) J a m es W . Fredlock of th e M on ongalia-Prest on County Pharmaceutical G uild, Russell Lucas , director of th e poison control center , M ayor Charles W . Blissitt , wh o procla imed p oison control week , a nd Dean R .O . B achmann of t h e sch ool of pharma cy. In a ddition t o th e a ccomplishment s of the pra cticing ph arm acist s in M organtown, ph armacy students of W est Virginia U niversity initiat ed t h eir own serv ice a ctiv ities. Aft er a iding in th e coun t y-wide Sabin polio vaccine campa ign b y m easurin g th e vaccin e onto sugar cubes, students jumped into a civ il d efen se project . Sh own (lower right) with p art of the 20 tra iler load s of civ il d efen se supplies they unload ed ar e (left to right) Kenneth R. M a rtin, Thomas V. Kreitzer, J ohn R . Mullin , D ouglas E . Mill er , By ron M . Ott, Charles E . J a ckson , William A . Hurst a nd Ph arma cy D ean R .O. B achma nn . U nder th e a u spices of th e District of Columbia Pha rma ceutica l Association , severa l classes in th e " M edical Self-H elp T raining Progra m " of th e Ci vil D efense D epartment a re b eing given in W ashington , D .C . Currentl y a cting as instructor s ar e W a lter E . M ancuso, immediat e p ast president of th e loca l association, and R . D avid Allen, second vice presid ent. Below, M ancuso (left) directs two students in som e of th e t echnics of coping with radioa ctive fa llout, first a id a nd living conditions.
· · · · · · · lie- · ··· ,· .... · . · m eca..c; Ias.·.· ,• .• .• .• .• .• .• • • .• • • llA• • • • ,,··.......... •.••.••.•.."a.t~ i . . . .. I
.. . . . · . . . . .. tj ...• •
• • • • • •
..~
·• • .• •.• •.• • .• •.• • •• •8r~. JI ..· • • • • • •••
• • • • • • .c:. ~
• • • • • • • • • • •
n March 21, HEW Secretary Anthony J. Celebrezze approved licenses fo r manufacturing two types of measles vaccine. M erck , Sharp a nd Dohme was granted a license fo r a live attenuated m easles vaccine and Chas. Pfizer and Company, Inc., received a license t o market a killed-virus vaccine. Licen sing these two fo rms of measles vaccine brings t o a fo reseeable en d a nother contest between m an and virus which has lasted for hundreds of years. T he invidious measles virus, like its many deadly brothers, is immune to ant ibiotics, too small to be caught with an ordinary microscope and controllable only by t he body's own defenses. The on ly offense against it, t herefore, is a strong defense- t o make t he body resist ant before t he virus strikes . 11easles vaccine, capable of protecting m illions of children against the und errated disease, is t he newest achievement of immunology. Known medically as rubeola a nd morbilli, measles is an acute, highly contagious viral disease, with illness generally lasting fo ur to ten days. T he incubation period, from fi rst exposure unt il onset of symptoms, is seven to 14 days. F irst symptoms include feve r , a runnin g nose, sneezing, puffy eyelids and red eyes and a harsh bronchial cough. T hese are followed wit hin 24 to 48 hours by appearance of lesions or markings (K opEk 's spots) inside t he mouth on t he cheek 's m ucous membranes. Three t o five days after the onset of symptoms, t he telltale measles rash appears- a distinctive dusky-red , blotchy skin eru ption which st arts behind the ears a nd on the fo rehead , extends t o t h e fa ce, neck and t runk and finally reaches the a rms and legs. T he measles virus seems t o be transmitted entirely fro m person t o person , proba bly by infectious droplets fro m the nose and throat . T he pa tient can infect others fro m t wo t o four days before t he rash appears until two t o five days after it appears. 11easles antibodies u sually develop about this time (about three weeks after initial contact ). One attack generally gives th e victim lifelong immunity. 11easles attacks about 95 percent of the population of the United States. It is almost inevitable in childhood ; m ost people have had measles b y age 15. Wit h births currently
O
numbering about 4,200, 000 a year (4,282,000 in 196 1), the number of measles cases probably averages about 4,000 ,000 annually. No t too lon g ago, m easles was regarded m ore as a subject fo r humor than as the scourge it really is- cartoons of spotty-faced children t ypified the casu al attitude of the public t oward the disease. Its seriousness is sti11largely unrecognized t oday. Measles is, in fact, all t oo often a killer or the cau se of mental crippling and m ore than t wice as many children die each year from measles com plications as from poliomyelitis.
a small villain M easles is so widespread that it almost certainly exist ed in a ncient t imes yet t he first account of it did not appear until t he writ ings of Rhazes in the 10th century. By the Middle Ages it was common throughout E urope and Asia and was confused wit h , or associated with , other exanthemic (eruptive) diseases such as smallpox. By t he 16th century, physici ans were different iating it from the other eruptive diseases, giving it t he Latin name morbilli. The E nglish word mesles was a corrupt ion of t he Latin miselli (from miser) b ut which referred t o t he sores of leprosy, another confusion in t he medieval mind. And alt hou gh measles was fin ally distinguished from b oth leprosy and smallpox, it cont inued t o be confused with scarlet feve r until the en d of t he 18th cent ury . Measles came to America wit h t he colonists and t here were out breaks t hroughout the 16th a nd 17t h cent uries in many parts of Spanish America. In 1785 t here was a severe epidemic in Ec uador- more t han 2,400 died at Quito. Among t he F rench and Indians, a minor epidemic was reported in 1635 and a severe one in 1687 in Quebec. Bost on was hit in 1657 and again in 1687, the latter infect ion possibly having been bro ught in from Canada. This epidemic produced the first medical document printed in t he American colonies- A B rief R ·tle to Guide the Common-P eo ple of New England H ow to Order Them selves and Theirs in the S m all-P ocks or .ilI/easles- b y Thomas Thacher in which he continued the belief t hat the t wo diseases were relat ed. New E ngland had severe epidemics from 1713 t o 171 5 with 150 deaths at Bost on . Conn ect icut had a serious epidemic in 1740 and the other colonies were stru ck at intervals. Noah Webst er reported an outbreak in Charlestown , N ort h Carolina in 1772 in which " died 800 or 900 children ." Since one attack of measles produces a permanent immunity, the sparsely populated American colonies had fairly long res pites bet ween epidemics until new birt hs had increased t he population sufficiently for another crop of su sceptibles t o become available. By the end of the colonial period, t he settled areas of America were well seeded wit h measles virus. From then on , measles followed the tide of empire westward and the pattern of epidemics spread throu gh K entucky and Ohio with the pioneers. In modern times the epidemics occur at usual intervals of three to four years, mostly in the springtime. There may be localized outbreaks in the spring of off-years. During vVorld vVar II , measles was something of a military problem , Vol. NS3, No.5, May 1963
243
particularly in countries like Iceland and Greenland where large numbers of troops were quartered upon a population highly susceptible to the virus. Similarly, the disease has been very severe in Eskimos as it reached them.
One of the first steps in preparing the live-virus measles vaccine marketed by Merck Sharp and Do h m e is removing the emb ryos from the chicken eggs. This removal is done under a sterile hood .
When the heads and feet have been removed from the embryos (above), the embryos are ground into a mince and trypsinized (below). The mince is placed in flasks and trypsin is added to break down the m ince into in dividual cells or groups of cells.
searchers Attempts to control measles date back at least to 1758 when Francis Home at Edinburgh inoculated 12 children with blood from measles victims in the hope that he could induce a mild form of the disease which would confer immunity. The full cases of measles which developed in seven of the children demonstrated the transmissibility of the disease, but offered no hope that an attenuated form could be induced in this way. Hope for the control of measles was meager until the beginning of the 20th century. In 1911 John F . Anderson and Joseph Goldberger proved that measles is caused by a filterahle yirus. In 1938 Harry Plotz published his report on the successful growing of measles virus in tissue cultures and between 19;39 and 1943 the virus was cultivated in chick embryos by Geoffrey Rake and Morris Shaffer. Attempts to create a \raccine from this attenuated strain of virus were, however, unsuccessful. Enders breakthrough The way toward development of a practical, effective measles vaccine was opened in ] 95-l by Drs. John F. Enders and Thomas C. Peebles of Harvard Medical School. These scientists succeeded in culturing measles virus from the blood and throat washings of an ll-year-old boy named David Edmonston. The virus at first could he made to grow in laboratory cultures of monkey and human kidney tissue. Its presence could be demonstrated by the pathologic changes it caused in these cells. Dr. Enders and his associates subsequently grew the Edmonston strain in 24 successive cultures of human kidney tissue and then in 28 serial cultures of human amnion. At this point they managed to adapt it to fertilized hens' eggs and finally to single-layer cultures of chick-emhryo cells in laboratory glassware . The virus grew rapidly on the chickembryo tissue cuI tures. After a number of passages in the eggs and tissue cultures, tests shov,ed the virulence of the infecting agent had been weakened. In monkeys the virus caused a mild infection that stimulated the animals to form antibodies and the monkeys subsequently resisted infection by full-strength measles virus capable of producing disease in unvaccinated animals. In addition, there was no evidence of viremia, no recognizable infection of the central nervous system and no detectable ,-irus in the upper respiratory tract. \\Then given (in 1958) t o children who had not had measles, the attenuated virus produced only a mild form of the disease with significant development of measles antibodies. Hence, the Enders group had succeeded in developin g an attenuated-virus vaccine that promised to put an end to the 200-year search. From this point, the quest for a practical vaccine branched off into a number of parallel pathways, with some interesting side excursions. For example, it was found that distemper, a serious disease of dogs, is caused by a virus closely related to the measles virus and man has been found to have circulating antibodies to the canine agent. However, attempts to immunize man against measles with canine distemper vaccine have thus far been unsuccessful. Research is continuing 011 this interesting interviral relationship. By the latter part of 1961, there were several potential measles vaccines in various stages of preparation. \\There the search for a polio vaccine had produced first a killed-virus vaccine (Salk) and then a live vaccine (Sabin), measles research resulted in the development of both killed and live vaccines simultaneously. government approval Under the ~ ational Biologics Control Act, a license for the
manufacture and interstate distribution of vaccines, serums, antitoxins and similar biological products for medical use can be issued when the manufacturer demonstrates that his product meets federal standards of safety, purity and potency. Such products are tested and evaluated by the division of biologics standards of the National Institutes of Health, research arm of the Public Health Service. Over the last several years, the vaccines have been successfully tested both in this country and abroad. Nearly 50,000 children in the United States alone have received these vaccines in field trials. Secretary Celebrezze characterized the field trials as "a long and painstaking evaluation" and saidThis was made possible by the co-operative efforts of scientists-both in and out of government-by physicians, the pharmaceutical industry and thous ands of unselfish and courageous parent s who have permitted their children to participate in the field trials. This splendid teamwork between science, government, industry and the general public has scored a great victory for better child health which will be hailed in all countrie'5 and by all people .
live-virus vaccine Lyovac Rubeovax (Merck Sharp and Dohme) is a live attenuated measles vaccine, developed for single-dose immunization against the disease. The use of Rubeovax without the co-administration of immune serum globulin (human) standardized for measles antibody content may be accompanied by rash and fever, both of which may be severe. Therefore, Merck Sharp and Dohme has introduced Gammagee, an immune serum globulin (human) that has been standardized for its concentration of measles ~mtibodies for use in conjunction with Rubeovax, t o modif," the mild measles infection induced by the vaccine . Each immunization of Lyovac Rubeoyax is supplied in two packages- a 0.5 cc vial containing one dose of lyophilized vaccine and an accompanying, separate package containing a 0.7 cc ampul of sterile diluent and a plastic disposable syringe with needle for reconstitution and injection of the vaccine. Because the lyophilized vaccine must be kept at temperatures near freezing (no higher than five degrees C. or 41 degrees F.) while the diluent must not be frozen (to avoid breakage of the ampul), a special shipping container was developed by l\1"erck Sharp and Dohme to accommodate both at the proper temperatures. This container, of molded polystyrene , accommodates ten complete immunizations. It is divided into two compartments insulated from each other. One contains the vaccine and dry ice which will keep it at proper temperature for about 54 hours; the other contains the diluent and syringe and also space for Gammagee. The reconstituted Lyovac Rubeovax live attenuated measles vaccine , in a dose of 0.5 cc, is injected subcutaneously into the upper arm. Injection of the vaccine into the buttock has given poor results. Each 0.5 cc dose of reconstituted Rubeovax contains no less than 1,000 TCID 50 of measles virus vaccine expressed in terms of the assigned titer of the NIH reference measles virus. Gammagee immune serum globulin is administered in a dose of 0.01 cc per pound of body weight, injected immediately thereafter into the deltoid muscle of the opposite arm. Neither Gammagee nor Rubeovax should be injected intravenously. It is recommended that only children eight months of age and over be immunized since earlier immuni zation may not take due to maternal antibodies. Measles vaccine is contraindicated in individuals with leukemia and should be avoided in patients with active t uberculosis not yet under treatment. There is no indication for its administration to pregnant women in the hope of averting congenital anomalies. Any febrile respiratory illness or other active infection is reason for delaying use of the vaccine unless, in the opinion of the physician, withholding the agent entails even greater risk.
In clarifying measles vaccine, the pooled fluids are passed under pressure through filters (being adjusted by the techn icia n) which remove cellular material, then through an ice bath and then into an othe r pooling tank (foreground) to form an homogeneous vaccine .
Vials are filled with measles vaccine under sterile conditions. A measured amount of vaccine is delivered automatically through the tube for each vial. Ultraviolet light protects the operation and only one row of vials at a time is exposed for filling. When it is completed , the operator exposes an adjacent row by turning the handwheel. The vialed vaccine is then quick-frozen .
A small number of persons are extremely allergic to egg proteins and may show severe re actions to injections of a vaccine derived from chick embryos. Thus use of this, or any vaccine prepared from a medium containing chick protein, is absolutely contraindicated in persons with a hist ory of hypersensitivity t o egg, chicken or chicken feathers . Elective immunization should be deferred during an outbreak of poliomyelitis since there is indication it may result in localization of paralysis in the inoculated arm of those patients who may subsequently develop paralytic polio. U.S. Public Health Service Surgeon General Luther Terry Vol. NS3, No .5, May 1963
245
has endorsed the report of his ad hoc advisory committee recommending the use of the live vaccine, except under special circumst ances, because of its lon ger-las ting immunity after a single inj ection. T he live-virus vaccine does n ot require booster shot s as does t he killed vaccine. T he live-virus vaccine will reportedly prod uce ab ove 95 percen t protection .
kill ed vaccine
To make killed vaccine large quantities of pure virus are needed and these can be grown only In living cells . Techn icians at Charles Pfizer and Company laboratories fill large flasks with nutrient med ium and livin g cells which will be grown to serve as hosts for t he measles ·virus.
Chas. Pfizer and Company placed on t he market in April an inactivated (killed) measles virus vaccine, packaged initially in 10-dose vials. It can be stored under normal refrigerati on and will n ot require the use of gamma globulin with it since it will n ot produce t he reactions associated wit h t he u se of the live-virus vaccine, but it will require t hree inj ection s a mont h apart for com plete immunity. Clinical test s indicate that measles antibodies of a pr otective level were developed in between 90 and 95 percent of t hose receivin g either the three injections of inactivat ed vaccine or t he two inj ections of inactivated followed by one injection of attenuated live vaccine. T he Pfizer vaccine has been developed fr om t he E dmonston strain of virus isolat ed by J ohn Enders an d it is being produced at Pfizer's biological product ion center in Terre Hau te, Indiana. P hilli ps R oxane has developed a live-v irus measles vaccine which is m ade by growing its virus on dog kidney tissue. Philli ps Roxane claim s t hat dog kidney tissue has been fo und to be ge nerally free of t he wi ld viruses that sometimes plague vaccine m anufacturers. Because no other commercial vaccine has ever been grown on dog kid ney t issue, t he government is requiring considerably more testing on Phillips vaccine before it will be licensed. •
......... ........ ......... pol iomyel itis- 19S3 (continu ed from page 242)
A scientist examines cells grown by tissue culture technic (above). The microscope shows cells developing normally and free of invad ing orga nisms . They will se rve as host for the virus from wh ich th e vaccine will be m ade. Living cells grow in an incubator (below) at the virus laboratories of Pfizer. All operations are carried out under the strict est cond itions of st eril ity.
important purpose- focusing public attention on the whole question of how individual and community health are maintained and protected in our society. Public relations has been defined as " good deeds properly celebrated." T he definition cert.ainly applies here. The experience with polio has inevitably led to consideration of other forms of social action against other illnesses. Last year, the Congress passed legislat.ion to combat three other diseases of childhood- whooping cough, tetanus and diphtheri a. T itled the Vaccination Assistance Act, the legislation calls for aid to t he states to undertake t he vaccination of all children un der five, inclu ding t he fo ur m illion a nnual newborns, against t hese diseases and against polio. The present Congress has before it a request for fun ds to get t.his farreachin g, long-range progra m under way. Not all details have been worked out-·for funding, for administration or for the ve ry su bstantial and sustained job of public education that will be req uired by both t he U.S. P ublic Health Service a nd t he states. It is ob vious, however , t hat t he possibilit ies inherent in t his legislation are t remendous- ·na mely, t he fmal elimin ation of all fo ur of t hese ancient enemies of childhood. To stam p t hem out we will all have to travel a long, hard road and t he struggle will , qui te possibly, be fra ught with controversy. Bu t who would say that it will not be wor th every effor t we can pu t into it? Summer , t he season of childhood's freedo m , is no longer a season of fear fo r parents . "\Vho among those who h ave known t he skirmishes a nd alarms of t he polio battle- and who hasn 't- would wish to have not endured it or to fail in cont inuing to push fo rward toward fin al victory? •
From loca l t o n ationa l lev el, group effort a m ong pharma cist s is b eing geared t oward community serv ice. This effort was dr am atically highlighted in Abington ( P ennsy lvania) M emorial H ospita l during presentation of a p oison control cabinet by M ontgomer y County Pharma ceutical Association . A 19month old ba by, a cutely p oison ed b y ingestion of m oth ba lls, was rush ed into th e em ergency wa rd during th e cer em onies and t h e cabinet was put into immediat e u se b efor e it actually b eca me t he h ospita l's p ossession . Assisting in th e su ccessful t r eatment (above left) a r e M orris George, h ospita l a dministrat or, Rich ard B . Bitner, pr esident of t h e don ating association, Alonzo Sudler, Jr. , hospita l ph ar ma cist , Irvin R eich, presentation ch airman, Philip Seltzer, president of D elawar e Vall ey E thical Pra ctices Council , J oseph T . B earwood , Jr., MD, and N urse W orthington . Wiscon sin is a n other st at e striving for complet e coverage a ga inst a ll types of accidenta l p oisoning. T ypica l of th e m an y p oison control center s which h ave b een d onat ed b y Wiscon sin pharma cist s is this on e in Shawan o Community H ospita l (top right ). Th e center was presented by (left to right) Otto R ognlien , H arvey J ewel, H enry Cook a nd J ohn G allagh er. In M organtown , West Virginia community pharmacist s spon sor ed a prom otiona l campa ign during Nationa l P oison Control Week. As p art of t h e campaign th ey set up a p oison control center in th e em ergen cy r oom of West Virginia U niversity H ospita l. Checking the list of a ntidot es (center right) a r e (left to rig ht) J a m es W . Fredlock of th e M on ongalia-Prest on County Pharmaceutical G uild, Russell Lucas , director of th e poison control center , M ayor Charles W . Blissitt , wh o procla imed p oison control week , a nd Dean R .O . B achmann of t h e sch ool of pharma cy. In a ddition t o th e a ccomplishment s of the pra cticing ph arm acist s in M organtown, ph armacy students of W est Virginia U niversity initiat ed t h eir own serv ice a ctiv ities. Aft er a iding in th e coun t y-wide Sabin polio vaccine campa ign b y m easurin g th e vaccin e onto sugar cubes, students jumped into a civ il d efen se project . Sh own (lower right) with p art of the 20 tra iler load s of civ il d efen se supplies they unload ed ar e (left to right) Kenneth R. M a rtin, Thomas V. Kreitzer, J ohn R . Mullin , D ouglas E . Mill er , By ron M . Ott, Charles E . J a ckson , William A . Hurst a nd Ph arma cy D ean R .O. B achma nn . U nder th e a u spices of th e District of Columbia Pha rma ceutica l Association , severa l classes in th e " M edical Self-H elp T raining Progra m " of th e Ci vil D efense D epartment a re b eing given in W ashington , D .C . Currentl y a cting as instructor s ar e W a lter E . M ancuso, immediat e p ast president of th e loca l association, and R . D avid Allen, second vice presid ent. Below, M ancuso (left) directs two students in som e of th e t echnics of coping with radioa ctive fa llout, first a id a nd living conditions.