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Koja je efikasnost dopunske vakcine protiv pertusisa među različitim starosnim grupama?

Koja je efikasnost dopunske vakcine protiv pertusisa među različitim starosnim grupama?


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Knjiga Murray Microbiology kaže da je prefencijalno 10 godina, slično estonskim i finskim zdravstvenim udruženjima.

Međutim, moj profesor kaže da može i 5-7 godina.

Počeo sam da razmišljam da li godine ovde utiču na rezultat.

Kada treba da uzmete dopunsku vakcinaciju protiv pertusisa ako jeste a) 25 godina, b) 50 godina, v) 70 godina, i g) 90 godina?

Moj profesor kaže da ne postoje značajne studije o efikasnosti dopunske vakcinacije protiv pertusisa među različitim starosnim grupama. Да ли је ово истина?


Ne, nije tačno, pogledajte reference 1 i 2 za ovu svrhu. Из ових чланака који су пратили додатне вакцинације против хрипавца чини се да постоји бар нека заштита 5 и 8 година након потицаја.

Постоји још једна студија, која каже да је за 10 година релативно сигурно претпоставити, јер би смањење нивоа антитела током времена процењено из петогодишње студије и даље омогућило заштитне нивое антитела. Pogledajte referencu 3 za detalje.

Један од проблема приликом давања изјава о трајању заштите је недостатак података. Pored toga, došlo je do promene vakcine iz cele ćelije (koja je prilično imunogena, ali ima veći broj neželjenih nuspojava) u odnosu na acelularnu vakcinu. Ova promena se dogodila 90-ih godina, tako da nema dostupnih dugoročnih podataka. Pogledajte referencu četiri za više detalja.

Uobičajena preporuka u ovom trenutku za odrasle je ponavljanje dopunske vakcinacije svakih 10 godina (zajedno sa tetanusom i difterijom), a za osobe koje imaju blizak kontakt sa nevakcinisanim osobama svakih 5 godina da bi se sprečile infekcije (videti referencu 4).

Референце:

  1. Имунитет на кашаљ 5 година након додатне имунизације током адолесценције.
  2. Imuni odgovori na antigene pertusisa osam godina nakon buster imunizacije acelularnim vakcinama kod odraslih.
  3. Koliko dugo možemo očekivati ​​da će zaštita od pertusisa trajati nakon adolescentne buster doze vakcina protiv tetanusa-difterije-pertusisa (Tdap)?
  4. Primena acelularne vakcine protiv pertusisa u rizičnim grupama (adolescenti, trudnice, novorođenčad i zdravstveni radnici): Pregled dokaza i preporuka

Вакцине за децу - Водич за родитеље и неговатеље

Вакцине су допринеле значајном смањењу многих заразних болести у детињству, попут дифтерије, оспица и Haemophilus influenzae тип б (Хиб). Neke zarazne bolesti, poput dečije paralize, eliminisane su u Sjedinjenim Državama zahvaljujući efikasnim vakcinama. Uz visoku stopu vakcinacije, sada je retko da deca u Sjedinjenim Državama dožive razorne i često smrtonosne posledice nekih zaraznih bolesti koje su nekada bile uobičajene u Sjedinjenim Državama i drugim zemljama.

Vakcine za prevenciju zaraznih bolesti daju se milionima beba, dece, adolescenata i odraslih i od ključne je važnosti da se pokaže da su bezbedne i efikasne. Osiguravanje sigurnosti i efikasnosti vakcina jedan je od glavnih prioriteta Uprave za hranu i lijekove (FDA). Центар за биолошку евалуацију и истраживање (ЦБЕР) је центар у оквиру ФДА који има регулаторни надзор над вакцинама у Сједињеним Државама, осигуравајући доступност сигурних и ефикасних вакцина.

Pošto su programi imunizacije u 20. i 21. veku bili tako uspešni, mnogi današnji roditelji nikada nisu videli mnoge bolesti koje se mogu sprečiti vakcinom i ne razumeju potencijal da se ponovo pojave. Ako previše pojedinaca odluči da ne vakciniše sebe ili svoju decu, neke bolesti koje su sada retke ili nepostojeće u ovoj zemlji mogu se ponovo pojaviti.

Virusi i bakterije koje izazivaju bolesti i smrt koje se mogu sprečiti vakcinama i dalje postoje i mogu izazvati bolest kod ljudi koji nisu zaštićeni vakcinama. Na primer, iako boginje nisu bile stalno prisutne u Sjedinjenim Državama od 2000. godine i koje su te godine proglašene eliminisanim u SAD, slučajevi i epidemije i dalje se javljaju. То се приписује различитим факторима, укључујући уобичајену појаву оспица у многим дијеловима свијета, невакцинисане путнике са оспицама који доносе болест у Сједињене Државе из других земаља, те ширење оспица у заједницама у САД -у у којима групе ljudi su nevakcinisani. САД су затвориле 2018. годину са укупно 17 избијања оспица, а случајеви су се наставили појављивати и у 2019. 2019. означава највећи број пријављених случајева оспица у САД -у од 1992. године и од када је оспице проглашено елиминисаним 2000. године. oko 10% zahteva hospitalizaciju. Najveći broj slučajeva je među osobama koje nisu vakcinisane protiv morbila.

Morbile su jedna od najzaraznijih bolesti i mogu izazvati teške komplikacije, uključujući upalu pluća, oticanje mozga i smrt. Epidemije zaraznih bolesti, poput morbila, služe kao podsetnik da je do njih samo vožnja avionom i najbolji način da se ne razbolite jeste da se vakcinišete.


Da li je vakcina protiv pertusisa u detinjstvu manje efikasna nego što smo mislili?

Да бисте поново прегледали овај чланак, посетите Мој профил, а затим Прегледајте сачуване приче.

Da biste ponovo pogledali ovaj članak, posetite Moj profil, a zatim Pogledajte sačuvane priče.


Delikatno i oprezno, zdravstvene vlasti u Sjedinjenim Državama i drugim zemljama počinju da otvaraju tešku temu: da li je vanredna tekuća epidemija velikog kašlja, najgora u poslednjih više od 50 godina, delom posledica neočekivano lošeg učinka вакцина за спречавање болести.

Та могућност, обухваћена у неколико недавних истраживања - једном објављеном синоћ - поставља се тако пажљиво јер би могла навести противнике вакцине да погрешно тврде да вакцинација против хрипавца не функционише. Taj strah sadrži duboku ironiju: trenutna vakcina, koja se koristila oko 20 godina, zamenila je stariju i efikasniju koja je izašla iz upotrebe jer su kritičari vakcine optužili da ima previsoku stopu neželjenih efekata.

У најновијем истраживању, писму објављеном у уторак увече у ЈАМА-и, истраживачи из аустралијског Куеенсланда испитивали су учесталост хрипавца код деце која су рођена 1998. године, године у којој је та провинција почела постепено укидати вакцину против целичног хрипавца (познату као tamo kao DTwP) u korist manje reaktivne acelularne vakcine (poznate kao DTaP). Deca koja su rođena te godine i koja su primila kompletnu seriju vakcinacija protiv pertusisa kod novorođenčadi (sa 2, 4 i 6 meseci) možda su dobila celu ćeliju, sve-bez ćelije ili mešavinu - i zbog odličnog vođenja evidencije državnog zdravstvenog sistema, istraživači su uspeli da potvrde koja deca su primila koje vakcine. (Napomena: Deca iz Kvinslenda, kao i deca u SAD, takođe dobijaju pojačivače posle serije za bebe, zajedno sa poslednjim boosterom u svojim predtinejdžerskim godinama.)

Istraživači su bili podstaknuti da istraže jer, kao i SAD, Australija trpi žestoku epidemiju hripavca. Kada su pregledali istoriju bolesti za 40.694 dece čija je istorija vakcine mogla biti verifikovana, pronašli su 267 slučajeva pertusisa između 1999. i 2011. Rekli su:

Deca koja su primala primarni kurs DTaP od 3 doze imala su veće stope obolevanja od pertusisa od one koja su primala primarni kurs DTwP od 3 doze u periodima pre epidemije i izbijanja. Među onima koji su primali mešovite kurseve, stope u trenutnoj epidemiji bile su najveće za decu koja su primala DTaP kao prvu dozu. Ovaj obrazac je ostao kada se posmatraju podgrupe sa 1 ili 2 doze DTwP u prvoj godini života, iako nije dostigao statističku značajnost. Deca koja su primala mešoviti kurs sa DTwP kao početnom dozom imala su stope incidencije koje su bile između stopa za kohorte DTwP čistog kursa i DTaP.

Ova cifra iz papira prikazuje različite rezultate:


Pertussis je cikličan, sa vrhuncem koji se javlja svake tri do pet godina, ali autori (koji dolaze iz Odeljenja za medicinska istraživanja dece Univerziteta Kvinslend) kažu da je efekat koji su otkrili opstao i tokom perioda „pre-epidemije i izbijanja“. Oni priznaju da je moguće da cirkulišući sojevi bakterije velikog kašlja, Бордетелла пертуссис, možda se promenio tokom više od decenije otkako su vakcine zamenjene, ali kažu da je najrazumnije objašnjenje da imunološka zaštita koju daje DTaP ne traje toliko dugo kao ona od starije vakcine.

Ova mogućnost je ranije bila istaknuta. Prošle jeseni, na godišnjem sastanku ICAAC o infektivnim bolestima, lekari iz medicinskog centra Kaiser Permanente u San Rafaelu, Kalifornija, izvestili su da primećuju neočekivano visoku količinu pertusisa kod potpuno vakcinisanih predtinejdžera koji još nisu primili svoju poslednju dozu. . Од 171 детета које је ПЦР дијагностиковало да болују од 2010. године, 132 је било између 8 и 14. Они су тада рекли да је стопа хрипавца у пред-тинејџерској групи била "скоро 20 пута већа" него код недавно вакцинисаних предшколаца. ponovo je splasnuo kod dece starije od 12 godina koja su primila poslednju dopunu -- i pitali su se da li zaštita DTaP vakcine slabi ranije nego što se očekivalo i ostavlja predtinejdžere ranjivim na infekciju. (Tabela iz njihovog sažetka je desno.)

Dovođenje u pitanje efikasnosti vakcina, usred epidemije i dok su pod izazovom religioznih i "ličnih" izuzeća, zvuči kao jeres - ali u stvari, Centri za kontrolu i prevenciju bolesti tek su nedavno pokrenuli tu mogućnost. Agencija je 20. jula objavila izveštaj o epidemijama u državi Vašington (gde su slučajevi porasli za 1.300 odsto u odnosu na prošlu godinu) i na nacionalnom nivou. Izveštaj je sadržao široko rasprostranjen i dramatičan grafikon krive epidemije - ali je takođe uključivao i ovaj manje reprodukovan grafikon, koji ilustruje razliku u incidenciji između grupa vakcina sa celim ćelijama i grupe vakcina bez ćelija, što podseća na podatke iz Kvinslenda:

**Uporedo sa grafikonom, u izveštaju se primećuje:

Acelularne i ceoćelijske vakcine imaju visoku efikasnost tokom prve 2 godine nakon vakcinacije, ali nedavne promene u epidemiologiji pertusisa u Sjedinjenim Državama snažno sugerišu smanjeno trajanje zaštite koju pruža acelularna vakcina za decu (DTaP) u poređenju sa onim od difterije i tetanus toksoidi i vakcina protiv pertusisa celog ćelija (DTwP). Od sredine 2000-ih, incidencija pertusisa kod dece uzrasta od 7 do 10 godina porasla je. Štaviše, uočeno povećanje rizika po godinama života od 7 do 10 godina sugeriše kohortni efekat povećanja osetljivosti jer ona deca koja su isključivo primala acelularne vakcine nastavljaju da stare.


Rezultati

Karakteristike studija

Od 28 pozvanih zemalja, 18 zemalja se složilo da učestvuje i poslalo oko 250 uzoraka za obe ciljane starosne grupe od 40–49 i 50–59 godina u RIVM. Карактеристике збирки узорака, као што су период прикупљања (2015–2018) и локације, сажете су у Табели 1. Расподјела узорака по полу добијена је из 16 земаља. Da bi se izbegla pristrasnost izbora, svi uzorci (N = 1644) iz dve starosne grupe prikupljene u nacionalnoj studiji sero-nadzora u Holandiji su uključene. Podaci iz UK obuhvataju uzorke samo iz Engleske. Укупно је укључено 10.302 предмета.

Prevalencija antitela za pertussis

Укупни проценти серума по земљи са нивоом ИгГ-ПТ ≥ 100 ИУ/мЛ варирали су између 0,0% (Финска) и 9,7% (Норвешка), при чему 13/18 земаља показује ниво између 2,7 и 5,8% (Сл. 1 и Tabela 2). Nivoi između 50 i 100 IU/mL za IgG-PT (Tabela 2) kretali su se između 4,8% (Ujedinjeno Kraljevstvo) i 9,9% (Francuska) za sve zemlje, isključujući Norvešku sa nivoom od 12,5%. Procenat subjekata bez antitela koja se detektuju, IgG-PT < 0,85 IU/mL, varirao je između 2,0% (Norveška) i 9,8% (Grčka) (Tabela 2). Seroprevalencija (IgG-PT ≥ 100 IU/mL) dve starosne grupe odvojeno i ukupno po zemlji je ilustrovana na Slici 2 sa podelom po polu. Nismo pronašli nikakav uticaj starosti i pola na ukupnu seroprevalencu (str = 0,846 и str = 0,802 odn.), ali je efekat zemlje bio značajan (str = 0,023, Dodatna tabela 1). Za ukupnu seroprevalencu nivoa IgG-PT 50-100 IU/mL, takođe nije pronađen nikakav efekat na starost i pol (str = 0.212, str = 0,082 odnosno 0,082, a efekat zemlje je ostao značajan (str = 0,007), dok su za nivo IgG-PT ≥50 IU/mL sve tri kategorije bile značajne (str = 0.038, str = 0.020, str & лт 0,001, Допунска табела 1). Вредности геометријске средње концентрације (ГМЦ) за антитела ИгГ-ПТ кретале су се од 7,2 до 14,8 ИУ/мЛ у 18 земаља (Табела 3). Značajne GMC razlike između starosnih kohorti pronađene su za Austriju, Litvaniju, Letoniju, Holandiju i Norvešku sa povišenim koncentracijama IgG-PT u kohorti od 50–59 godina, osim za Austriju (Tabela 3). Između pola, značajne GMC razlike mogu se uočiti u ukupnoj kohorti za Finsku, Mađarsku, Holandiju, Portugal i UK sa povišenim koncentracijama IgG-PT kod muškaraca (dodatna slika 1).

IgG-PT (а), IgG-Dt (б) i IgG-TT (ц). Proporcija seroprevalencije pertusisa podeljena na uzorke <0,85 IU/mL (žuta), 0,85 do <50 IU/mL (zelena), 50 do <100 IU/mL (plava) i ≥100 IU/mL (ljubičasta) i serozaštita i protiv difterije tetanus u <0,01 IU/mL (ljubičasta), 0,01 do <0,1 IU/mL (zelena) i ≥0,1 IU/mL (žuta) u 18 zemalja. Zbirka šipki je do 100%. Скраћенице свих земаља учесница и број узорака укључених у студију наведени су у Табели 1.

На Икс-osom je prikazan procenat seroprevalencije za PT ≥ 100 IU/mL. Tačke označavaju procenjenu seroprevalencu, a trake odgovarajuće intervale poverenja od 95%. Procene i str вредности разлика добијају се биномским генерализованим линеарним регресионим моделом, у коме се модификована функција логит везе користи за исправљање специфичности од 0,98 и осетљивости од 0,78. Skraćenice svih zemalja učesnica i broj uzoraka uključenih u studiju navedeni su u tabeli 1.

Prevalencija antitela za difteriju

Udeo seruma sa nivoima Dt antitela ispod osnovnog nivoa imuniteta od 0,01 IU/mL varirao je između 4% (Finska) i 43% (Grčka), a za zaštitni nivo od 0,1 IU/mL od 23% za Finsku do oko 80 % za Grčku, Irsku, Rumuniju i Ujedinjeno Kraljevstvo (Slika 1 i Tabela 2). Старост, пол и земља имали су значајан утицај на серозаштиту за оба гранична пресека (str < 0,001, Dodatna tabela 1). Značajne razlike u odnosu na pol unutar zemalja pronađene su za nivoe <0,01 IU/mL u grupama od 40–49 godina za Dansku, Holandiju i Švedsku, kod 50–59 godina za Mađarsku, Holandiju, Slovačku Republiku i Sjedinjene Američke Države. Kraljevine i u ukupnim kohortama za Dansku, Mađarsku, Holandiju, Slovačku i Ujedinjeno Kraljevstvo (Sl. 3). Za nivoe <0,1 IU/mL razlike u polu su nađene kod 40–49 godina za Dansku, Francusku, Mađarsku, Irsku i Holandiju, kod 50–59 godina za Dansku i Holandiju, i ukupno kohorte za Dansku, Francusku, Irsku i Holandiju. GMC nivoa IgG-Dt su bili niski za sve zemlje učesnice, ne prelazeći 0,1 IU/mL u ukupnim kohortama za 11/18 zemalja (Tabela 3). GMC kod 50–59 godina uvek je bio niži od onih kod 40–49 godina, osim za Holandiju i Rumuniju podjednako nizak, a značajna razlika u GMC između starosnih grupa nađena je u 11/18 zemalja (Tabela 3 ).

На Икс-osa procenat nedostatka seroprotekcije protiv difterije za IgG-Dt <0,01 IU/mL (а) i <0,1 IU/mL (б) се приказује. Tačke označavaju procenjenu seroprevalencu, a trake odgovaraju odgovarajućim intervalima poverenja od 95%. Procene i str vrednosti razlika se dobijaju binomnim generalizovanim modelom linearne regresije sa funkcijom logit veze. Skraćenice svih zemalja učesnica i broj uzoraka uključenih u studiju navedeni su u tabeli 1.

Prevalencija antitela za tetanus

Za razliku od difterije, nivoi seroprotekcije za tetanus su bili dovoljni sa samo nekoliko seruma kojima nedostaje osnovni imunitet (Slika 1 i Tabela 2). Удео серума са нивоима испод 0,01 ИУ/мЛ кретао се од 0 до 1,2%, осим у Грчкој (2,4%). Za ukupnu kohortu, sedam zemalja je smatrano potpuno zaštićenim (Austrija, Finska, Francuska, Mađarska, Letonija, Portugal i Slovenija). Zaštitni nivo od 0,1 IU/mL dostignut je u više od 90% seruma u svim zemljama, osim u Grčkoj (79%) i Irskoj (83%). У осталих 16 земаља удео серума са незаштићеним нивоима (<0,1 ИУ/мЛ) кретао се од 0,4 до 8,2%. Dok su pol i država imali značajan uticaj na nivo seroprotekcije (<0,1 IU/mL, str ≤ 0,001), nije pronađen značajan uticaj na nezaštićenom nivou (str = 0.902, str = 0.986) str = 0,491, odnosno, Dodatna tabela 1). Između zemalja nisu nađene značajne polne razlike za nivo nezaštićenih u obe starosne grupe i u ukupnoj kohorti (Sl. 4). Međutim, za nivo seroprotekcije polne razlike su pronađene u starosnoj grupi 40–49 godina za Švedsku, u 50–59 godina za Dansku, Mađarsku, Irsku i Letoniju i u ukupnim kohortama za Belgiju, Dansku, Mađarsku, Irsku, Letonija i Švedska. GMC IgG-TT je bio iznad 1,0 IU/mL u 14 zemalja u rasponu od 1,15 do 3,16 IU/mL, a ispod 1,0 IU/mL u četiri zemlje u rasponu od 0,36 do 0,83 IU/mL. U 13 zemalja GMC u starosti od 50–59 godina bio je niži nego kod 40–49 godina. Značajne razlike u GMC između starosnih grupa pronađene su u Francuskoj, Grčkoj, Letoniji i Rumuniji (Tabela 3).

На Икс-osi procenat nedostatka seroprotekcije protiv tetanusa za IgG-TT < 0,01 IU/mL (а) i <0,1 IU/mL (б) се приказује. Тачке означавају процењену серопреваленцију, а шипке одговарајуће интервале поузданости од 95%. Процене и str vrednosti razlika se dobijaju primenom egzaktnih binomnih metoda. Скраћенице свих земаља учесница и број узорака укључених у студију наведени су у Табели 1.


Analiza isplativosti različitih strategija vakcinacije protiv pertusisa prvenstveno usmerenih na zaštitu odojčadi u Holandiji

Pozadina: Pertussis je veoma zarazna respiratorna bolest. Uprkos visokoj stopi pokrivenosti vakcinom kroz holandski nacionalni program imunizacije, incidenca pertusisa i dalje je visoka u Holandiji i rizik od infekcije se nastavlja. Pošto je pertussis najteži kod neimunizovane novorođenčadi i odojčadi koja su primila samo neke od preporučenih doza, treba razmotriti nove strategije imunizacije protiv pertusisa kako bi se zaštitila ova ugrožena populacija.

Циљ: Ова студија је осмишљена да процени исплативост 3 нове стратегије имунизације за могући додатак постојећем холандском националном програму имунизације: имунизација одојчета при рођењу, имунизација родитеља непосредно након рођења детета (чачкање) и imunizacija majke tokom trećeg trimestra trudnoće.

Metode: U bazi podataka PubMed izvršena je pretraga literature za članke objavljene na engleskom, nemačkom i holandskom uz korišćenje sledećih termina: pertusis, veliki kašalj, strategije vakcinacije, imunizacija majke, začahure, pri rođenju, efikasnost vakcine, mortalitet, nedovoljno prijavljivanje, prevalencija , učestalost i isplativost. Za ovu analizu razvijen je model stabla odluka, a podaci o oboljevanju od pertusisa i troškovima su prikupljani dosledno za različite starosne grupe (odojčad

Rezultati: U analizi osnovnog slučaja, utvrđeno je da su čahura i imunizacija majke efikasne u smanjenju incidencije pertusisa kod novorođenčadi (očekivalo se da će se sprečiti 123 i 174 slučaja odojčadi, respektivno). Štaviše, procenjeno je da su čahura i imunizacija majki isplativi iz perspektive platioca ((sic)4600 [6400 USD]/QALY i (sic)3500 [4900 USD]/QALY, respektivno), pa čak i da uštede troškove iz perspektive društva (uštede do (sic)7200 [10,100$] i (sic)5000 [7000$], respektivno). Analize osetljivosti su otkrile da je povoljna isplativost generalno bila čvrsta. U analizi osetljivosti, isplativost čahure i imunizacije majki je uglavnom bila osetljiva na promene u pretpostavkama o nedostatku prijavljivanja (200 puta povećanje broja prijavljenih simptomatskih slučajeva) bolesti pertusisa i infekcije. Bez manjih prijava, ICER je procenjen na (sic)211,900 (296,700$)/QALY za čahuru i (sic)81,600 ($114,200)/QALY za imunizaciju majke iz perspektive platiša. Međutim, čak i pri mnogo nižim nivoima nedovoljnog prijavljivanja (20 do 30 puta povećanje incidencije), isplativost je ostala povoljna. Isplativost treće strategije, imunizacije pri rođenju, bila je veoma nepovoljna ((sic)329,900 [461,900$]/QALY iz perspektive platioca i (sic)330,100 [8462,100]! QALY iz perspektive društva).

Zaključci: U ovoj studiji je procenjeno da bi dodavanje vakcinacije ili imunizacije majke trenutnom holandskom nacionalnom programu imunizacije verovatno bilo isplativo ili čak uštedelo. Ове процене су углавном последица смањења броја случајева међу родитељима, који ће вероватно бити благи и стога ће углавном остати непријављени. Imunizacija pri rođenju nije bila isplativa strategija. Cocooing je bila najskuplja intervencija za implementaciju, međutim, rezultirala je najvećim brojem QALY dobijenih (uglavnom kod odraslih). Имунизација мајке би понудила бољу заштиту одојчади, због мајчински стечених антитела. (Clin Ther. 201032:1479-1495) (C) 2010 Excerpta Medica Inc.


Vakcina protiv velikog kašlja: Snaga prvog utiska

Sadašnja vakcina protiv velikog kašlja je univerzalno usvojena u SAD 1996. godine da zameni originalnu vakcinu zasnovanu na mrtvim Бордетелла пертуссис због јачег сигурносног профила. Utvrđeno je da je nova formulacija efikasna u prevenciji velikog kašlja tokom ranjivih faza u životnom veku, ali vrsta vakcine protiv pertusisa koja se koristi za jačanje imunološkog sistema ostavlja trajni utisak. У свом најновијем истраживању, истраживачи са Института за алергију и имунологију Ла Јолла (ЉИ) известили су да појединци који су инокулирани новијом вакцином у оквиру своје почетне серије ињекција, имају слабији одговор при опозиву када касније добију потиске. "Видимо драматичан ефекат утискивања у зависности од тога да ли су људи примили стару или нову вакцину против хрипавца као део своје првобитне вакцинације у детињству", каже професор биологије ЉИ Алессандро Сетте, др Биол. Сци., Шеф Одељења за откривање вакцина. „Čak i ako su dopunske vakcine koje su primili kao srednjoškolci ili kao odrasli sadržavali istu vakcinu, imuni sistem i dalje ima veoma upečatljivo sećanje na ono što je video tokom prve imunizacije.

Otkrivanje razlika između ove dve vakcine je ključno za razumevanje kako bolje sprečiti veliki kašalj i takođe može pružiti važne lekcije o efikasnosti vakcine uopšte, potencijalno primenljive na druge vakcine. Konkretno, studija, koja bi trebalo da bude objavljena u Јоурнал оф Цлиницал Инвестигатион, otkrili su da nova vakcina nije uspela da generiše robustan odgovor T ćelija, koji obezbeđuje dugoročnu memoriju koja omogućava imunom sistemu da brzo odgovori ako je izložena patogenu. "U idealnom slučaju, trebalo bi da angažujete obe ruke zaštitnog odgovora protiv patogena - B ćelije koje proizvode antitela i T ćelije koje stvaraju dugoročnu memoriju", kaže prvi autor Rikardo Antunes, doktor nauka, postdoktorski istraživač u laboratoriji Sette. . "Али очигледно да нова вакцина не успева да произведе одговарајући Т -ћелијски одговор."

Tradicionalno, sposobnost indukovanja visokog titra antitela bila je merilo na osnovu kojeg su merene vakcine. „Iako su B ćelije veoma važna komponenta efikasnosti vakcine, važna uloga T ćelija se sve više ceni i ključna tačka naše studije je da pokažemo da postoje upadljive razlike u odgovoru T ćelija na dve različite vakcine. “, kaže Antunes. Bordetella pertussis, bakterija koja izaziva veliki kašalj, proizvodi toksin koji izaziva nekontrolisane, ponekad smrtonosne napade kašlja. Pre nego što je vakcina postala dostupna, veliki kašalj je ubio hiljade ljudi i prouzrokovao da se stotine hiljada obole iz godine u godinu. Sa uvođenjem prve vakcine, koja je napravljena od mrtvih bakterija, slučajevi su dramatično opali, ali neželjeni neželjeni efekti preparata cele ćelije (wP) doveli su SAD i mnoge druge zemlje da pređu na acelularne (aP) formule koje su se oslanjale na prečišćene bakterijske proteini za izazivanje imuniteta. Vakcinacija protiv ove bolesti trenutno uključuje seriju od pet vakcina datih maloj deci u dobi od 2, 4 i 6 meseci, negde između 15 i 18 meseci, i petu dozu između 4 i 6 godina i poslednju dozu između 11 i 12 godina. година стар. Trudnice primaju jednu injekciju u trećem tromesečju trudnoće kako bi zaštitile novorođenčad, populaciju sa najvećim rizikom od komplikacija pertusisa. Uprkos dodatnim injekcijama, broj slučajeva velikog kašlja poslednjih godina počeo je da raste, a do 2015. godine prijavljeno je više od 20.000 slučajeva širom zemlje.

Pošto su se godine rođenja tinejdžera i mladih odraslih osoba koje su najviše pogođene naglim porastom slučajeva pertusisa poklopile sa prelaskom na nacionalnom nivou sa wP vakcine na aP vakcinu, postavilo se pitanje da li nova formulacija vakcine pruža manju zaštitu.

Da bi potražio odgovore, tim LJI je regrutovao 114 zdravih odraslih osoba koje su prvobitno bile ili vakcinisane sa wP ili aP u detinjstvu i davale su dopunske vakcinacije sa aP u srednjoj i srednjoj školi i kao odrasle osobe i analizirale njihov imuni odgovor u redovnim intervalima. Njihovi rezultati su jasno pokazali da primena u prvih nekoliko meseci nakon rođenja sa aP ili wP vakcinama izaziva različite odgovore T ćelija. Iako su oba u početku sposobna da generišu zaštitni imunitet, razlike se razvijaju tokom više od 15 godina.

Pored suptilnijih promena u populaciji B ćelija i sekreciji citokina, T ćelije koje su prvobitno bile pripremljene sa aP postepeno gube sposobnost da reaguju na dopunsku vakcinaciju. „Ove ćelije samo sede i ne rade ništa, dok T ćelije napunjene wP reaguju sa izraženim pojačanjem“, kaže Antunes. Detaljne transkriptomske analize otkrile su smanjenu aktivnost gena povezanih sa proliferacijom ćelija.

„Pošto možemo da vidimo jasne razlike u imunološkim potpisima izazvanim dvema različitim vakcinama u roku od nekoliko dana nakon pojačavanja, ovo sugeriše da bi potencijalni put napred bio testiranje da li bi nove vakcine mogle da reprodukuju zaštitniji potpis“, kaže Sette .


Zaključci

Избијање хрипавца је примећено у популацији у којој је већина појединаца завршила курс ДТаП вакцине као одојчад. AR je bio veći kod učenika koji nisu završili kompletan kurs DTaP vakcine za bebe. Процењује се да је ефикасност вакцине била 52%, нижа од оне описане у претходним извештајима о деци, највероватније због смањења нивоа антитела у дугом временском периоду од њихове последње дозе ДТаП. Ови резултати указују на неопходност додатне вакцинације за тинејџере и развој високо ефикасних вакцина против хрипавца.


Rezultati

Препоруке за вакцинацију пре 1991

U DDR-u je vakcinacija protiv hripavca bila obavezna za svu decu od 1964. godine [16]. Осамдесетих година прошлог века препоручене су три дозе целијске вакцине у доби од 2, 3 и 6 месеци. Четврта доза је препоручена у трећој години живота [20]. Između 1971. i 1979. godine preporučena je peta doza pre polaska u školu [21, 22].

У ФВГ -у рутинска вакцинација против хрипавца вакцином са целијом ћелијом препоручена је за одојчад и малу децу од 1969. до 1974. године [16]. Kao iu nekim drugim zemljama, kao što je Velika Britanija, STIKO je ovu preporuku povukao od 1974. [23] do 1991. godine zbog anegdotskih izveštaja o teškim štetnim efektima koji utiču na centralni nervni sistem. Tokom ovog perioda, vakcinacija protiv hripavca se preporučuje samo za decu visokog rizika pre njihovog drugog rođendana.

Обухват вакцинацијом пре 1991

Pokrivenost vakcinacijom dece predškolskog uzrasta (≥ 4 doze) bila je >90% u GDR tokom 1980-ih [20]. Ankete i procene zasnovane na podacima o prodaji vakcina tokom 1970-ih i 1980-ih u FWG-u otkrile su pokrivenost vakcinacijom dece od 50-60% u južnim i 2-20% u severnim regionima [24].

Incidenca pertusisa pre 1991

Incidencija pertusisa na osnovu prijavljenih slučajeva u DDR-u opala je na <1/100.000 populacije u kasnim 1980-im pre ponovnog ujedinjenja [25, 26] (Slika 1). Procene incidencije u FWG zasnovane na regionalnim istraživanjima iz 1970-ih i 1980-ih kretale su se od 160–180 slučajeva/100.000 stanovnika [25, 27]. Među decom starije od 6 godina, incidencija pertusisa je procenjena na 4%–6% godišnje između 1987. i 1990. godine [28].

Incidencija prijavljenih obolelih od hripavca (1947–2007) i hospitalizacija (1993–2007) u Nemačkoj, (GDR: Nemačka Demokratska Republika, FEG: Bivša Istočna Nemačka, FWG: Bivša Zapadna Nemačka).

Preporuke za vakcinaciju posle 1990

Godine 1991. vakcinaciju protiv hripavca za svu odojčad celoćelijskom vakcinom protiv hripavca ponovo je preporučio STIKO u ujedinjenoj Nemačkoj, sa četiri doze vakcine u dobi od 2, 3, 4 i 11 do 14 meseci [29]. STIKO je 1993. godine preporučio nadoknadnu vakcinaciju za svu decu do njihovog šestog rođendana [30]. Godine 1995. u Nemačkoj su licencirane acelularne vakcine sa 2 (toksin pertusis (PT) i filamentni hemaglutinin (FHA)), 3 (PT, FHA i pertaktin (PRN)) ili 5 komponenti (PT, FHA, PRN i fimbrije 2 i 3). . Oni su isključivo preporučeni od 1997. godine. Godine 2000. preporučena je jednokratna dopunska vakcinacija za decu uzrasta od 9 do 17 godina [31]. STIKO je 2003. godine preporučio vakcinaciju protiv hripavca za radnike u nezi dece i zdravstvene radnike [32], a 2004. godine dodatno za odrasle koji su u bliskom kontaktu sa bebama (roditelji i drugi negovatelji) pre rođenja deteta (strategija čahure) [33]. Dodatnu dozu u uzrastu od 5-6 godina preporučio je STIKO u januaru 2006. U Saksoniji, Državni komitet za vakcinaciju (SIKO) je preporučio dopunsku dozu za predškolsku ustanovu već 1998. godine i dopunsku vakcinaciju za odrasle u intervalima od 10 godina 2007. [34].

Обухват вакцинацијом након 1990

Prihvatanje vakcine protiv pertusisa se samo postepeno povećavalo u FWG nakon 1991. pre širokog uvođenja acelularnih vakcina 1995. godine, koje su se isključivo preporučivale od 1998. nadalje. U FEG unos vakcine se zapravo smanjio između 1991. i 1995. Anketa intervjua koju su sproveli Kirschner et al. 1994–1995 [35] је открио обухват вакцинацијом у доби од 2 године (најмање 4 дозе вакцине) од 8,8% (деца рођена 1989.) и 46,6% (деца рођена 1992.) у ФРГ и 65,5% (деца рођена у 1989) and 46.3% (children born in 1992) in FEG. Of children born in 1992, 92.5% had begun the vaccination series in FEG but only 76.7% in FWG. From 1998 until 2007, vaccination coverage of children at school entry increased steadily in FEG from 85.8% to 95.9% and in FWG from 57.7% to 92.2%.

Vaccination coverage was also assessed in the recent German Health Interview and Examination Survey for Children and Adolescents (KiGGS), which examined a representative sample of 17,461 children from 0 to 17 years between May 2003 and May 2006, of whom 16,460 (93.1%) presented their vaccination record [36, 37]. Pertussis vaccination coverage (at least 4 vaccine doses) was 84.9% (95% CI: 81.7%–87.6%) at the age of 2 years and peaked at 90.4% (95% CI: 89.2–91.5%) in 3 to 6 year old children (FEG: 91.9% (95% CI: 89.9–93.5%), FWG: 90.1 (95% CI: 88.7–91.3%). In older children, vaccination coverage decreased markedly with age to 36.1% (95% CI: 32.0–40.4%) in 14 to 17-year old adolescents, who had a significantly higher vaccination coverage in FEG (FEG: 78.8% (95% CI: 73.3%–83.5%) than FWG: 23.1% (95%CI: 20.0%–26.4%). Adolescents aged 14–17 years had also received the recommended booster vaccination more frequently in FEG (39.5% (95% CI: 34.6%–44.7%)) than in FWG (13.3% (95% CI: 11.0%–16.0%)). Only 10% of 14–17 year olds not vaccinated at a younger age had received at least one dose of pertussis-containing vaccine. In Saxony, vaccination coverage with a 5 th vaccine dose in 7–8 year-old children reached 71.5% in 2006 (unpublished data DB). Vaccination coverage data for the preschool booster recommended in 2006 in all other states are unavailable thus far.

Pertussis incidence in former East German States after 1990 based on surveillance data

Decreasing vaccination coverage after reunification in the early 1990s in FEG was associated with an increase in pertussis incidence to 3.4 cases/10000 inhabitants in 1994 (Fig. 1). Following a slight decrease in incidence from 1995 to 1997, pertussis incidence increased further, despite the STIKO recommendation for a booster vaccination at the age of 9 to 17 years in 2000 [38]. In 2007 pertussis incidence in FEG climbed to 39.3 notified cases/100.000 inhabitants. Regionally, the increase in incidence was less marked and occurred later in Saxony-Anhalt (ST) and TH as compared to BB and MV (Fig. 2). The increase in incidence after 2002 was most evident in children aged 5 to 9 and 10 to14 years, among whom incidence was highest, reaching >300 cases/100,000 inhabitants in BB and MV (Fig. 2). However, the incidence increased in infants (>3-fold in the five states) and adults as well. In SN, the overall incidence was lowest and a marked increase in incidence – most pronounced among 10–14 year olds – did not occur until 2007 (Fig. 2). The proportion of notified pertussis cases reported as hospitalized from 2002–2007 was lowest in BB (1.9%) and MV (2.2%) and higher in ST (4.9%), TH (4.1%) and SN (4.6%). Hospitalization was reported for 39.5% of infants <1 year, 4.4% for 1–4 year old children, 1.9% of 5–59 year old individuals and 5.8% of persons ≥ 60 years.

Pertussis incidence in former East German States 2002–2007 based on notification data according to state-specific infectious disease surveillance laws.

Sex and age distribution

Available surveillance data from 1995 onwards in FEG consistently showed a higher pertussis incidence in females (overall 60% of cases) than in males. This difference was mainly due to a higher proportion of females among adult cases.

An analysis of the age distribution of cases from 1995 to 2007 in the FEG states reveals a marked decrease in the proportion of cases among under 5-year olds, and, until 2003, also a decrease in the proportion of cases among older children and adolescents. While this development was largely sustained in Saxony until 2006, in the other 4 FEG states the proportion of cases among school children (5 to 14 year olds) increased markedly in 2004 (Fig. 3a &3b). The age distribution also shows that the absolute burden of disease is currently greatest in adults. In Saxony, the proportion of adults (>19 years of age) among all cases increased from 16.7% in 1995 to 80.3% in 2005 (subsequently decreasing 67.8% in 2007), while in the other 4 FEG States this proportion increased more gradually from 21.1% in 1995 to 68.7% in 2007, also reflected by the increase in mean age of reported pertussis cases over time (Fig. 3a &3b)

Age distribution of notified pertussis cases in the former East German States Brandenburg, Mecklenburg Western Pomerania, Saxony Anhalt and Thuringia (Fig. 3a), and Saxony (Fig. 3b) 1995–2007. The total number of cases is shown on top of the bars. Age-specific data for 2000 are incomplete and no age specific data are available for 2001.

Vaccination status of pertussis cases reported in former East German States, 2004–2007

FEG surveillance data from 2004 onwards reveal a high proportion of adequately vaccinated cases among children aged 6 to 11 years (Fig. 4). Among notified cases with information on vaccination status in BB, MV ST and TH, the proportion of cases aged 6 to 11 years with ≥4 previous vaccine doses was 59%, 61%, 67% and 68% in 2004 to 2007 respectively, while this was 13%, 22%, 30% and 63% in SN (80/99 adequately vaccinated cases from Saxony were reported in 2007). In BB, MV, ST and TH, only 5.3% (73/1384) of these cases had been vaccinated within the 3 years preceding their illness while in SN, this applied to 27.3% (27/99) of vaccinated cases, most of which were diagnosed in 2007 (20/27, all by PCR). Of all 4842 cases with at least one documented dose of pertussis vaccine in FEG from 2004–2007, 746 (15.4%) had been vaccinated < 3 years prior to illness onset (4.1% of all notified cases).

Incidence of notified pertussis cases in the former East German States Brandenburg, Mecklenburg Western Pomerania, Saxony Anhalt and Thuringia (Fig. 4a), and Saxony (Fig. 4b), 2004–2007, according to age and vaccination status.

Outbreaks

From 2002 to 2007, 16.0% of notified pertussis cases in FEG were reported as epidemiologically linked 9.4% occurred in clusters of 5 or more cases. The largest cluster that occurred in MV in 2005–2006 consisted of 80 notified cases, but active case-finding during an outbreak investigation identified a further 24 persons who fulfilled the clinical case definition [19]

Pertussis morbidity in both parts of Germany based on hospital discharge statistics, mortality data and sentinel surveillance in adults

Hospital discharge statistics show a decrease in pertussis hospitalizations in FEG from 1993 to 2001 with some fluctuation, decreasing from 1.5 pertussis related hospitalisations/100.000 population in 1993 to 0.6 in 2001, only to increase again to 1.7 in 2007 (Fig. 1). The number of hospitalizations in FWG decreased from 5.6/100000 population in 1993 to a low of 0.8 in 2001, increasing again to 1.5 in 2005 (Fig. 1). Between 2002 and 2007 the proportion of all pertussis-based hospitalizations among infants decreased from 66.6% in 2002 to 59.7% in 2007 in FWG, while it fluctuated between 22.5% (2007) and 28.9% (2006) in FEG, with a much higher incidence of infant hospitalizations in FWG (Fig. 5). Among older children and adults, however, incidence of hospitalization for pertussis was slightly higher in FEG than FWG. From 2002–2007 in FEG, 69.1% more cases were recorded in the German Hospital Discharge Statistics (n = 959) than cases notified as having been hospitalized (n = 567) in the statutory surveillance system. Until 2007, the incidence of hospitalized pertussis cases aged <1 year based on hospital discharge statistics was higher than the total incidence based on notified cases in FEG (see Fig. 2 and Fig. 5).

Hospitalizations for pertussis per 100.000 inhabitants according to age and residence in former East (FEG) and West (FWG) Germany, 2002–2007 (Source of data: Statistics of hospital diagnoses, Federal Statistical Office, available at http://www.gbe-bund.de/gbe10/abrechnung.prc_abr_test_logon?p_uid=gast&p_aid=&p_sprache=D&p_knoten=VR&p_suchstring=pertussis.

Between 1970 and 2007 nine deaths attributed to pertussis were reported in FEG, four of which occurred since 2002, all in elderly adults [39]. In FWG, 231 deaths were reported in this period, with mortality gradually decreasing. The last three deaths were reported in 2001 in an infant, in 2005 in an elderly woman and the third in 2007 in a teenager [39]. Mortality is depicted in Figure 1.

Sentinel surveillance in general physician and internist practices for cough illness lasting at least 7 days in adults (≥ 18 years) was performed in the FEG city of Rostock and the FWG city of Krefeld from 2001 to 2004 [40]. Among the 971 patients recruited to the study, 10% had pertussis based on a positive PCR of nasopharyngeal aspirate and/or positive serology (elevated IgA- and IgG-antibodies against pertussis toxin and filamentous haemagglutinin). The incidence of pertussis based on this study was estimated at 169 cases/100,000 inhabitants per year in Krefeld and 160/100.000 inhabitants per year in Rostock, with an estimated 110.000 cases occurring in adults annually in Germany. This was 19-fold higher than the mean incidence in adults based on routine surveillance in FEG from 2002–2004 of 8.5 cases/100,000 inhabitants respectively.

See additional file 1 for summary of the development of surveillance practices, vaccination recommendations, vaccination coverage and disease burden in the two parts of Germany.


Increase in pertussis outbreaks linked with vaccine exemptions, waning immunity

July 11, 2017 – A significant jump in the number of pertussis cases in the U.S. may be due to increasing numbers of nonmedical vaccine exemptions as well as waning immunity among those who have been vaccinated, according to a new study from Harvard researchers.

The incidence of pertussis, or whooping cough—a highly contagious respiratory illness that sends people into coughing fits and which can be deadly, particularly in babies—declined significantly over the course of four decades after a vaccine was introduced in the late 1940s. But the number of cases started creeping back up in the 1980s and 1990s, then increased dramatically in the mid-2000s. In 2012, there were 48,000 reported cases of pertussis in the U.S.—the highest number since 1955.

For the new study, the researchers—Carlin Aloe, Martin Kulldorff, and Barry Bloom—looked at five states that had pertussis rates in 2012 that were above the national average and for which there was detailed county-level data. For each county, researchers compared the incidence of pertussis with the number of nonmedical vaccine exemptions. They also looked at pertussis clusters among two different age groups—5 years and younger and 10-14 years.

“There were likely multiple reasons for these outbreaks,” said Bloom, Joan L. and Julius H. Jacobson Research Professor of Public Health at Harvard Chan School and senior author of the study, which was published online June 20, 2017 in PNAS (Proceedings of the National Academy of Sciences). “Our paper shows two things. One is that when you look at counties that have a lot of pertussis cases, they are the same counties that also have a high level of vaccine exemptions, which suggests an association between the two. Our other finding is that 10- to 14-year-olds who had been vaccinated were as susceptible to pertussis as kids who had never been vaccinated—suggesting that the vaccine’s effectiveness was not long lasting.”

Non-medical vaccine exemptions have been on the rise over the past two decades, with many parents declining vaccines for their children because they believe that vaccines aren’t safe—although substantial evidence points to the contrary, Bloom said.

In addition, a growing body of research suggests that some vaccines, previously thought to confer long-term protection against diseases such as pertussis, measles, and mumps, actually lose effectiveness over time.

Given the study’s findings, officials in states with high pertussis rates may want to rethink their policies on nonmedical vaccine exemptions, said Bloom. While not all of the counties with high rates of vaccine exemptions experienced pertussis outbreaks, they are clearly at risk for outbreaks in the future, he said.

Lead author Carlin Aloe, who received the 2016 Dean’s Prize for the outstanding thesis in biology at Harvard University Extension School, noted that only two states in the U.S., Mississippi and West Virginia, don’t allow nonmedical vaccine exemptions—and pertussis rates in those states are much lower than the states studied in the paper.

Federal officials may also want to consider revising recommendations for pediatricians on when and how often to give pertussis vaccines, said the researchers. “Our work suggests that maybe we should revaccinate teens to boost their immunity,” Bloom said.


The problem of waning pertussis immunity

Without a doubt (to me, at least), the biggest difference between science-based doctors and quacks is a very simple one. When a treatment or preventative measure isn’t working as well as it should, we science-based physicians ask why. We try to find out what is not working optimally and why. Then we try to figure out how to make things better. So it is with the acellular pertussis vaccine. This vaccine protects against whooping cough, which is caused by Bordetella pertussis, and is administered to children in the form of a combination vaccine, the DTaP (diphtheria/tetanus/acellular pertussis). Five doses are recommended for children, the first at age 2 months, and then at ages 4 months, 6 months, 15-18 months, and 4-6 years. There is also the newer formulation, the Tdap (tetanus, diphtheria, and acellular pertussis), which is recommended for people between the ages of 11 and 64. The Tdap is now usually administered first at age 11-12, with additional recommendations for a Tdap booster in adolescents and adults summarized here, here, and here. Unfortunately, although the vaccine works, recent outbreaks have suggested that we need to change our approach to pertussis vaccination. Let’s see why.

The resurgence of pertussis

It’s no secret that recent outbreaks have been notable for a large contingent of vaccinated children being affected, as has been pointed out in three recent studies. All three indicate that there appears to be a hole in the vaccination schedule that leaves children in the 9-12 year age range inadequately protected against pertussis. Two of these studies suggest that in that age group the attack rate during the recent outbreak in California the attack rate among vaccinated children approached that of unvaccinated children. Antivaccinationists love to cite these studies as smoking gun “proof” that the acellular pertussis vaccine “doesn’t work” and that “natural immunity is better,” but what they always leave out are the findings that the acellular pertussis vaccine in DTaP is quite effective in protecting younger children and in protecting teens who have received the recommended Tdap booster at age 11 or 12. The problem, it appears, is mostly in the range between the last DTaP dose, usually administered around age five or so, and the Tdap booster dose recommended for preadolescents.

First up, let’s look at a study study published last March examining the California pertussis outbreak by David J. Witt and colleagues at Kaiser Permanente. This study found a shorter-than-expected duration of immunity due to the the acellular pertussis vaccine. Basically, as I mentioned before, this study found that the vaccine was highly effective in children between 6 months and five years of age but that its effectiveness waned. The most disturbing part of the study was that it found that that vaccinated children between 10 and 12 were almost as likely to develop pertussis during the outbreak as unvaccinated children:

Among the 58 cases of pertussis in children aged 10-12, 55 (95%) had received five or more doses of pertussis vaccination. Eight of these 58 (14%) children had received their sixth booster-dose prior to onset of disease. In the 13-18 year age group and in the entire cohort of those 2-18 years of age, there was a highly significant increase in cases in unvaccinated children (p = 0.009 and 0.01 respectively). See table 1.

It should be noted that in all age groups, the attack rate in the unvaccinated and undervaccinated groups were higher than in the fully vaccinated group, but that this difference only reached statistical significance in the 13-18 year group, where the attack rate was nearly five times higher in the unvaccinated/undervaccinated group. Moreover, when taken as a whole, the attack rate was also statistically significantly higher in unvaccinated/undervaccinated children from ages 2 to 18. In other words, the vaccine works, but there is a period (age 10-12) during which there appears to be a hole in the coverage, such that waning immunity after the last dose results in decreased protection, protection that is reactivated by the booster dose at 12 years. Indeed, there was a very strong correlation between the interval between onset of pertussis and last acellular pertussis vaccine dose, with the interval peaking at 11 years. The authors conclude:

In the case of the recent California epidemic, it appears that the effectiveness of the current vaccine schedule, when paired with the imperfect vaccination rate, may be insufficient to prevent an epidemic. Earlier vaccine booster doses may be required to provide adequate herd immunity, absent an increase in vaccination rate, efficacy, or durability. Earlier booster doses could prevent immunity from waning, and address disease in the 8-12 age group.

In other words, this study doesn’t show that the vaccine doesn’t work. Rather, it suggests that immunity from the vaccine wanes sooner than expected, that this region of California doesn’t have a high enough vaccine uptake rate to prevent epidemics, and that the vaccination schedule should probably be changed to provide earlier boosters in order to protect older children and teenagers. Indeed, an accompanying editorial by Dr. Alfred DeMaria, Jr. agrees:

Continued widespread outbreaks of pertussis in the United States, with disruption of school and work, as well as with the significant threat to infants, begs the question of more effective use of Tdap on a population level. Experience with Tdap vaccine has diminished concerns about adverse events [12], but the duration of protection with Tdap is not yet known. Reasonable consideration should be given to the suggestion of earlier, more frequent booster doses, as well as the replacement of Td by Tdap as the routine adult “tetanus shot” [13, 14]. With US adolescent Tdap coverage of 69% [15], there is still more to do to achieve full implementation of current recommendations.

Indeed, the second study I mentioned, a study by Winter et al published in July in the Journal of Pediatrics more or less agrees. Basically, it found similar results, specifically a stepwise increase in pertussis among children aged 7-10 years who had completed the DTaP series but who had not yet received the Tdap booster recommended at age 11-12 years, along with a stepwise decrease in cases among adolescents from ages 11 to 14. The authors concluded that preadolescents are susceptible to waning immunity with the current schedule and that the adolescent Tdap dose is effective in protecting younger adolescents.

Again, the conclusion is not that the vaccine doesn’t work, but rather that, given the limited duration of immunity from the acellular pertussis vaccine, our current vaccination schedule is probably not aggressive enough, particularly in children aged 6 to 10, where another booster would likely be a good idea. Moreover, what antivaccinationists tend to completely ignore are observations that, although vaccinated children can still be susceptible to pertussis, they are less infectious, have milder symptoms and shorter illness duration, and are at reduced risk for severe outcomes, such as requiring hospitalization.

Finally, hot off the presses in the current issue of the NEJM is a third study, also out of Kaiser Permanente, that starkly quantifies the waning immunity due to acellular pertussis vaccination. It was a case-control study, in which the authors examined Kaiser Permanente Northern California members who received a pertussis PCR test between January 2006 and June 2011, a time period that includes the last pertussis outbreak in California in 2010. Cases included children who were positive for pertussis and negative for parapertussis by PCR during the study period who also received a fifth dose of DTaP between the ages of 47 and 84 months. These cases were compared to two control groups. The first group consisted of “children who were PCR-negative for both pertussis and parapertussis and who received a fifth dose of DTaP before receiving a negative test result (the PCR-negative controls),” and the second group consisted of “health-plan members who were matched to each PCR-positive child (the matched controls).” Basically, to boil it down to its essence, children diagnosed with pertussis and who had pertussis confirmed by PCR were compared to children who were negative for pertussis on PCR and then to the general population of health plan members. This was a highly vaccinated population (99%), which did not differ between cases and controls. Overall, the study population ended up consisting of 277 children between the ages of 4 and 12 years who were PCR-positive for pertussis, 3,318 PCR-negative controls, and 6,086 matched controls.

One of the big advantages of an health care organization like Kaiser Permanente is that it’s very large (3.2 million members in just Northern California alone) and its databases provide a complete electronic medical record that includes vaccinations and laboratory tests, as well as inpatient, emergency department, and outpatient diagnoses. All of this allows for analyses that would be difficult to carry out otherwise, also because it’s all one health system with standardized care guidelines, which reduces heterogeneity in delivery of care. This is thus about as good as it can get doing epidemiological studies. Also, Kaiser’s members exhibited incidences of pertussis among the various age ranges whose pattern mirrors the patterns observed in the previous two studies I discussed:

During the period from January 2010 through June 2011, when 95% of the cases of pertussis in the study population were diagnosed, the incidence of pertussis was 115 cases per 100,000 person-years among members younger than 1 year of age, decreasing to 29 cases per 100,000 person-years at 5 years of age, sharply increasing to 226 cases per 100,000 person-years at 10 and 11 years of age, sharply decreasing until 15 years of age, and remaining low in persons 15 years of age or older (Figure 1).

In other words, there’s a higher incidence among babies under one year old that decreases through age five but then increases again, peaking at age 10 and 11, before decreasing again. Again, this is consistent with waning immunity of the last DTaP dose at around age 5 or 6. It was a waning of immunity that the authors could quantify:

In the primary analysis comparing PCR-positive children with PCR-negative controls, with adjustment for calendar time, age, sex, race or ethnic group, and medical service area, the odds ratio for pertussis was 1.42 per year (95% CI, 1.21 to 1.66), indicating that each year after the fifth dose of DTaP was associated with a 42% increased odds of acquiring pertussis. A secondary analysis comparing PCR-positive cases with matched controls yielded similar results (Table 2).

In this study, the risk of pertussis increased by 42% each year after the fifth DTaP dose. If DTaP effectiveness is initially 95%, so that the risk of pertussis in vaccinated children is only 5% that of unvaccinated children, then the risk would increase after 5 years by a factor of 1.425 to 29% that of unvaccinated children. The corresponding decrease in DTaP effectiveness would be from 95% to 71%. The amount of protection remaining after 5 years depends heavily on the initial effectiveness. If the initial effectiveness of DTaP was 90%, it would decrease to 42% after 5 years. Regardless of the initial effectiveness, the protection from disease afforded by the fifth dose of DTaP among fully vaccinated children who had exclusively received DTaP vaccines waned substantially during the 5 years after vaccination.

So, basically, what these three studies indicate is that we have a problem with the pertussis vaccine. The question then becomes: What to do about it?

Putting it all together

With respect to vaccines, antivaccinationists frequently willfully invoke the fallacy of the perfect solution (also known as the Nirvana fallacy), which I like to liken to an old sketch Mike Myers back when he was on Saturday Night Live in which he played a Scotsman who would loudly say, “If it’s not Scottish it’s crap.” Basically, under this fallacy, antivaccinationists will argue, in essence, that if a vaccine doesn’t work perfectly 100% of the time, it’s crap. If it isn’t absolutely, positively, 100% safe, it’s crap. If it fails, even just once, to protect against the disease it’s designed to protect against, it’s crap. Never mind that nothing in medicine is 100% effective and safe and that the only certainty in medicine (and life) is that all of us will one day die.

None of this is to say that we shouldn’t strive to improve the acellular pertussis vaccine or improve the vaccine schedule, and that was the topic of a recent paper in the New England Journal of Medicine by Dr. James D. Cherry, a pediatrician at the David Geffen School of Medicine, University of California at Los Angeles, Los Angeles entitled Epidemic Pertussis in 2012 — The Resurgence of a Vaccine-Preventable Disease. He begins by noting that in the U.S. we are currently experiencing what may turn out to be the largest outbreak of pertussis in 50 years, asking the question: Why has this vaccine-preventable disease been on the upswing in recent years? Several answers are forthcoming, but here’s a graph of pertussis versus time:

Cherry first points out that whooping cough is a cyclical disease, with major epidemics every two to five years in the pre-vaccine era. Although vaccination was wildly successful in reducing the incidence from 157 per 100,000 in the 1940s to 1 per 100,000 in 1973, infection does not, contrary to the claims of antivaccinationists that “natural immunity” is permanent, produce lifelong immunity neither does the vaccine. Cherry notes that this is in marked contrast to, for example, measles, for which immunity due to the vaccine lasts much longer. So now, even though there isn’t as high an incidence of whooping cough, the causative organism, Bordetella pertussis is still circulating in a manner similar to the way it did in the pre-vaccine era. Until recently, it just wasn’t causing epidemics the way that it did before.

Cherry tells us that there are actually two relevant issues to consider: The epidemiology of reported pertussis cases and the epidemiology of pertussis infection. He notes that existing studies suggest that 13 to 20% of prolonged coughs in adolescents and adults are likely due to B. pertussis infection, and studies examining antibody titers suggested an infection rate between 1% and 6%. In other words, there’s a lot of mildly symptomatic pertussis out there, which leads Cherry to ask:

So what are the causes of today’s high prevalence of pertussis? First, the timing of the initial resurgence of reported cases (see graph) suggests that the main reason for it was actually increased awareness. What with the media attention on vaccine safety in the 1970s and 1980s, the studies of DTaP vaccine in the 1980s, and the efficacy trials of the 1990s comparing DTP vaccines with DTaP vaccines, literally hundreds of articles about pertussis were published. Although this information largely escaped physicians who care for adults, some pediatricians, public health officials, and the public became more aware of pertussis, and reporting therefore improved.

Antivaccinationists will no doubt scoff at this suggestion the same way that they scoff at any suggestion that the increased prevalence of autism over the last 20 years could possibly be due to greater awareness and intensive screening programs, but as I’ve pointed out before, it’s a truism in medicine that whenever you look for a disease or condition more carefully you will always find more of it than you did before—sometimes a lot more, particularly if you use more sensitive tests or broaden the diagnostic criteria (the latter of which was done for autism in the early 1990s). As I discussed in the link above, examples abound in medicine in which screening campaigns and more sensitive diagnostic tests have resulted in an apparent increase in prevalence in diseases and conditions without any evidence of a “real” change in their prevalence, as asymptomatic and less symptomatic cases were picked up.

Cherry suggests that one factor behind the rise in pertussis lately is similar:

Moreover, during the past decade, polymerase-chain-reaction (PCR) assays have begun to be used for diagnosis, and a major contributor to the difference in the reported sizes of the 2005 and 2010 epidemics in California may well have been the more widespread use of PCR in 2010. Indeed, when serologic tests that require only a single serum sample and use methods with good specificity become more routinely available, we will see a substantial increase in the diagnosis of cases in adults.

One notes that the last study I cited used the PCR test exclusively to confirm a diagnosis of pertussis infection. Be that as it may, some of what’s going on here might just be overdiagnosis, in which mildly symptomatic cases or cases that aren’t that serious are picked up that once might have been dismissed as a persistent “crud.” Clearly, though, that’s not the only thing going on. Two other issues are likely also contributing. The first is what the three studies I just discussed document, namely waning immunity from the acellular pertussis vaccine. Cherry cites five studies showing that the old DTP (the whole cell pertussis vaccine combination with the tetanus and diphtheria vaccine) was more efficacious than the DTaP (the acellular pertussis vaccine combination), as well as two of the studies above.

Ironically, it is important to remember that the switch from the DTP combination vaccine (nowadays frequently abbreviated DTwP, to denote the whole cell pertussis vaccine) to the DTaP vaccine was largely driven by concerns about the safety of the DTP back in the 1980s stoked by a deceptive bit of muckraking in the form of a documentary written and produced by Lea Thompson entitled DPT: Vaccine Roulette, which first aired on a local NBC affiliate in Washington DC on April 19, 1982, and then ultimately was aired nationally on The Today Show. The documentary linked the whole cell pertussis component of the DTwP to encephalopathy through a series of horrific anecdotes of children who developed severe neurological issues after the DTP. Later, Harris Coulter and Barbara Loe Fisher (yes, that Barbara Loe Fisher, who also around the same time founded the antivaccine group the National Vaccine Information Center) wrote a book, DPT: A Shot in the Dark, further inflamed fears about the DPT vaccine being linked to encephalopathy that later studies failed to confirm, as Steve Novella described. So, in essence, a highly effective vaccine was traded in for a vaccine that’s also effective, but doesn’t provide immunity that is as long lasting, all because of fears of reactions that turned out not to be a risk of the original whole cell pertussis vaccine. To be fair, it’s clear that the DTwP caused more fevers and other side effects, but current evidence doesn’t support the link between the DTwP and really severe neurological complications, such as encephalopathy.

Finally, we should consider the potential contribution of genetic changes in circulating strains of B. pertussis.4 It is clear that genetic changes have occurred over time in three B. pertussis antigens — pertussis toxin, pertactin, and fimbriae. In fact, changes in fimbrial agglutinogens related to vaccine use were noted about 50 years ago. Studies in the Netherlands and Australia have suggested that genetic changes have led to vaccine failures, but many people question these findings. If genetic changes had increased the rates of vaccine failure, one would expect to see those effects first in Denmark, which has for the past 15 years used a vaccine with a single pertussis antigen (pertussis toxin toxoid). To date, however, there is no evidence of increased vaccine failure in Denmark.

These are the observations behind the claims by cranks like Mercola that vaccines are “causing dangerous mutations.” While it is possible that the B. pertussis bacteria is developing “resistance” to the vaccine through natural selection, the evidence that it is doing so strikes me as rather weak and preliminary. Even if it were, the answer would be to change the vaccine in order to include the evolved antigens. After all, do we decide that antibiotics as a class of drugs don’t work when bacteria evolve resistance or that chemotherapy as a class of drugs doesn’t work when tumors manage to do the same? That’s a rhetorical question, of course. Some segments of the alt-med world do, indeed, do just that, but reasonable scientists and physicians do not. They work to overcome that resistance.

Leaving aside that hypothetical problem that might be contributing to pertussis epidemics in the era of the acellular vaccine, what can be done to bring these epidemics under control? First, Cherry notes that the purpose of vaccination against B. pertussis is not to eliminate all disease. It’s to prevent serious disease (whooping cough) with its potentially horrific complications, up to and including death, particularly among young infants. One possible approach to deal with the issue of waning immunity of the DTaP vaccine would be to start it at a younger age with shorter intervals between doses. Another strategy might be to immunize pregnant women in order to reduce the risk that the mother will acquire pertussis around the time of delivery, with the added bonus that it would give the infant some protection for a month or two through maternal antibodies.

The point of course is that these recent epidemics, while they point to problems with the current vaccination schedule, do not by any means demonstrate that the vaccine doesn’t work or that it’s failed. Commenting on the current pertussis outbreak in Washington, the CDC put it in a recent MMWR:

The ongoing pertussis epidemic in Washington reflects the evolving epidemiology of pertussis in the United States. Although acellular pertussis vaccines provide excellent short-term protection, early waning of immunity might be contributing to increasing population-level susceptibility. Nevertheless, vaccination continues to be the single most effective strategy to reduce morbidity and mortality caused by pertussis. Vaccination of pregnant women and contacts of infants is recommended to protect infants too young to be vaccinated. In light of the increased incidence of pertussis in Washington and elsewhere, efforts should focus on full implementation of DTaP and Tdap recommendations to prevent infection and protect infants.

I also have one final point. While the evidence that pockets of unvaccinated children are the nidus for measles outbreaks is compelling, these latest pertussis outbreaks do not appear to be correlated with pockets of unvaccinated children. Certainly, none of the studies I’ve cited indicate that unvaccinated children are a major cause of these outbreaks, although common sense suggests that the existence of pockets of unvaccinated children can’t be helping and is unlikely even to be neutral. Unvaccinated children are, after all, at a 23-fold increased risk of catching whooping cough, which allows for the degradation of herd immunity at the very least as well as providing a reservoir for the offending bug, and the first two studies I discussed indicate that for most age ranges unvaccinated and undervaccinated children are at a significantly increased risk of catching pertussis than fully vaccinated children the problem is primarily at one age range where waning immunity from the DTaP leaves a gap in immunity. However, in this case, as far as I’ve been able to tell, unvaccinated children do not appear to be the primary drivers of these most recent pertussis epidemics, as they are for measles outbreaks. We as science-based supporters of vaccination have to be careful not to overstate our case and blame antivaccinationists for these pertussis epidemics without adequate evidence. That only provides antivaccinationists ammunition to use against science-based vaccine policies.

It would be nice if antivaccinationists would do the same and not overstate their case. It would be even nicer if they wouldn’t use outright misinformation to argue their case. Of course, if they were to do so, then they wouldn’t be antivaccinationists anymore. The difference between science-based supporters of vaccination and antivaccinationists is simple. We face reality. Evidence and science matter to us. When vaccines do not function as well as we would like and try to fix it. Even with the problems with waning immunity due to acellular pertussis vaccine and even with these recent epidemics of pertussis, as Cherry reminds us, today’s incidence of pertussis is still about one twenty-third of what it was during a typical epidemic year in the 1930s. Don’t believe me? Then take a look at this presentation by Thomas Clark, MD, MPH about pertussis epidemiology and vaccination. This slide set includes a slide that puts the graph above from Cherry’s paper into proper context:


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