Porque não temos vacinas contra parasitas?

Apresentação em tema: "Porque não temos vacinas contra parasitas?"— Transcrição da apresentação:

1 Porque não temos vacinas contra parasitas?
Manoel Barral-Netto FIOCRUZ-Bahia e FAMEB-UFBA

2 Porque não temos vacinas contra parasitas?
O sucesso das vacinas Anticorpos neutralizantes O insucesso das vacinas Complexidade da RI adquirida além dos Ac; Sistema Imune Inato; Outros fatores que interferem na RI. Perspectivas O insucesso das vacinas e a evolução. 2

3 Vacinação

4 A era de Jenner As early as the 10th century AD, fluid from smallpox lesions or dried scabs from healing sores given to susceptible individuals to make them immune  variolation  India and China Variolation resulted in less severe disease than natural infection  nasty lesion at the inoculation site, blisters, mild rash, fever, myalgia, and lethargy, but mortality appeared to have been only 1% to 2%, and generalized scarring was also rare. Variolation worked, but the disadvantages were such that the medical profession as a whole remained skeptical.

5 1796 “The resemblance which the pustule thus excited on the
boy's arm bore to variolous inoculation, yet as the indisposition was barely perceptible, I could scarcely persuade myself the patient was secure from the smallpox. However, on his being inoculated some months afterwards, it proved that he was secure.” A further variolation five years later confirmed the maintenance of immunity. Jenner's paper was rejected by the Transactions of The Royal Society, so he published his “Inquiry” privately.

6 O nascimento da imunologia (1875-1910)
Pasteur : Pasteurella septica (cholera) attenuated in vitro, injection of attenuated bacteria protected chickens from the effects of virulent cultures (VACCINE). Koch: cholera vibrio, killed whole-cell bacteria vaccine. All that was needed: isolate the causative agent, establish Koch's postulates, attenuate or kill the agent, and immunize. Controversy  Early preparations were neither as safe nor as protective as claimed, production facilities, regulatory agencies not well developed + design of clinical trials left much to be desired. Significant professional reservations about vaccines and educated parents not convinced about the advantages of immunization as a whole.

7 Primeira vacinas contra bactérias (1910-1930)
Koch's isolation of the tubercule bacillus, the search for a tuberculosis (TB) vaccine began. Calmette and Guerin started with an isolate of TB from a cow 213 subcultures (13 years)  tried the culture orally in a newborn infant BCG. Given intradermally  effective in infants for the prevention of miliary TB and tuberculous meningitis. World War I - opportunity for the whole cell–killed bacterial vaccines (typhoid), systematic use x absence of a formal clinical trial. Bordetella pertussis  1923  formalin treatment of diphtheria toxin could render it harmless, preserving its immunogenic potential  toxoids  progressive introduction into industrialized countries (1930)  lowered the impact of both diphtheria and tetanus.

8 Primeiras vacinas contra vírus: 1930-1950
1930s was a heady period for isolation of disease-causing viruses, but tissue culture was still the realm of a few practitioners. Goodpasture + Burnet improvement of techniques for growing viruses and Rickettsiae in embryonated hen's eggs. Theiler: safe and effective live attenuated yellow fever vaccine, 17D and first-generation killed whole virus influenza vaccines and vaccines against typhus  important for troops in World War II. Formalin-killed mouse brain–derived Japanese B encephalitis vaccine was also effective.

9 Revolução da cultura de células 1950-1970
Salk's formalin-treated whole virus vaccine provided protection  to 1961, 300 million doses administered, polio declined dramatically. Cutter Incident - faulty production techniques  two lots of vaccine with inadequate formalin inactivation = 149 cases of polio. Development of live attenuated oral poliomyelitis vaccine of Sabin, first introduced in 1961  By 1965, had essentially replaced the Salk vaccine. Orally active, more convenient to use, and containing far fewer virions, much cheaper  Very rare reversions to neurovirulence, estimated at one case per 2.7 million doses of oral poliomyelitis vaccine administered) . Now – tetravalent vaccine available (measles – mumps – rubella - varicella)

10 Era molecular: Surface antigen of the hepatitis B virus (HBsAg) = a single protein as a vaccine  first vaccine manufactured through recombinant DNA technology. 350 million carriers of hepatitis B worldwide, 20% to 25% of carriers develop chronic liver disease, and a substantial proportion of these go on to primary hepatocellular carcinoma hepatitis B vaccine is the first anticancer vaccine in history. The great success of the hepatitis B vaccine  new era in genetic engineering approaches. Subunit capsular polysaccharide vaccines against Streptococcus pneumoniae, Neisseria meningitidis, and Hemophilus influenzae B (Hib)  licensed in the 1970s and early 1980s  conjugation of the carbohydrate antigens to a protein carrier, usually diphtheria or tetanus toxoid  effective T cell help and immunologic memory to develop.

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12 Polio Eradication Progress, 1988 - 2002
Slide Date: October 03 Certified Polio-free regions (113 countries) Not Certified but non-endemic (72 countries) Endemic with wild polio virus ( 7 countries) Source: WHO AFP surveillance database data from 192 WHO member states

13 Esquema vacinação 0-6a, US 2007
The Jordan Report, NIAID 2007

14 Esquema vacinação 7-18a, US 2007
The Jordan Report, NIAID 2007

15 Esquema vacinação adultos, US 2007
The Jordan Report, NIAID 2007

16 Vacinas disponíveis Tipo de vacina Vírus Bactérias Organismo morto
Polio, sarampo, caxumba, rubéola, varicela, febre amarela Tuberculose, febre tifóide Organismo atenuado Polio, influenza, raiva, Hepatite A Pertussis, febre tifóide, cólera Subunidades Hepatite B H. influenza B, pertussis, menigococos, pneumococos, febre tifóide 16

17 Mecanismo da Vacina contra a Varíola
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18 Resposta Efetora Humoral
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19 O insucesso das vacinas
Complexidade da RI adquirida para além dos Acs Linfócitos T CD8+; Sistemas de citocinas e quimiocinas; Linfócitos T multifuncionais; Memória dos linfócitos T; Sinais inibitórios. 19

20 Proteção Mediada por Células
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21 Resposta imune celular

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23 Basis for effective vaccination

24 CD4+ T helper subsets

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28 Comparação entre formulações de vacinas

29 Correlation of antigen‐specific CD8+ T‐cell quality and viral load
The black arcs highlight the fraction of the multifunctional (3–5‐expressing) CD8+ T cells within each response.

30 O insucesso das vacinas
O sistema imune inato Padrões de resposta Influência do SI inato sobre a RI adquirida; Outros fatores Aspectos do vetor; Co-infecções; Outras condições: gravidez, e.g. 30

31 Immune response to YF-17D

32 Imunogenicidade: PAMPs x PRRs (TLRs, similares a IL-1bR)

33 Plasticidade funcional de DCs:
Estimulação de diferentes PRRs pode estimular respostas adaptativas distintas. TLR Pulendram & Ahmed, 2006

34 Imunogenicidade: outros PRRs
MBL – reconhecimento de carboidratos, atua como opsonina, capaz de ativar a cascata do complemento. DC-SIGN – presente na superfície, reconhecimento de carboidratos Danger signal – sinal de estresse/injúria ou patógeno  liberação de proteínas do hospedeiro  potentes imunoestimuladores (alarmins – defensins e cathelicidins possuem atividade antimicrobiana E agem como imunoestimulantes).

35 Rosenberg et al 2004 35

36 Perspectivas em vacinas
Novos adjuvantes; Compreensão global dos fatores imunológicos: Assinatura moleculares; Integração entre aspectos imunológicos e não imunológicos. Systems biology 36

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41 PAMP AND AG PARTICULATE CODELIVERY: THE PERFECT MIX
Ag carriers 3 4 7 9 2 Polymeric particles Mineral salts, alum ISCOMS, virosomes, virus-like particles Liposomes Emulsion s PRR, TLR agonists AG + PAMP Immunostimulation Potential toxicity Pasariamos de los que favorecen la captura de ag a los inmunopotenciadores intrínsecos, y numerosos adyuvantes que ejercerían ambos efectos de forma intermedia. Así podemos ver las sales minerales como el alum, el casi unico autorizado en humanos y que forma parte de las vacunas contra la difteria, el tétanos o la hepatitis b; o las emulsiones como la O/W MF59 que se trata de una emulsión del aceite escualeno en agua (autorizada en europa) o de naturaleza A/O como la montanide 720 que se ha probado en una vacuna frente al virus de la gripe. En cuanto a los inmunopotenciadores intrínsecos la lista es muy larga y ahora se utilizan muchos sintéticos y se encuentran en ensayos clínicos, ademas se están estableciendo de forma definida su capacidad para generar patrones de respuesta inmune específica según el patógeno frente al que queremos vacunar. Entre los adyuvantes mas inertes encontraremos los sistemas particulados como son los liposomes o las micropartículas o nanopartículas, que o bien generan un depot o si su tamaño es el adecuado son capturados por las DC favoreciendo el procesamiento y la presentación. De aquí es intutivo deducir que el sistema perefcto sería un sistema particulado que transporte el ag junto con alguna señal estimulatoria, porque representa la combinación de ambos efectos y ademas permitiría localizar en las DC el efecto de los PAMP reduciendo su toxicidad potencial. CAMBIAR Y PONER FOTOS DE PARTICULAS Y UN ESQUEMA DE LOS TLR. THREE COMPONENT VACCINE MODEL

42 strategy that augments
ADJUVANT A TCR CD28 B7 MHC II APC Th cell Signal O Signal 1 Signal 2 ADJUVANT B ADJUVANT C PAMPs Polymeric particles Liposomes Emulsions (MF59) Mineral salts: Alum Cytokines CD40L AG + adjuvant Protein, peptides, DNA, RNA Any substance or strategy that augments the immune response against an Ag

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45 Perspectivas em vacinas
Novos adjuvantes; Compreensão global dos fatores imunológicos: Assinatura moleculares; Integração entre aspectos imunológicos e não imunológicos. Systems biology 45

46 Innate correlates of yF‐17D immunogenicity identified by systems biological approaches

47 Predictive signatures of gene expression for vaccines

48 Perspectivas em vacinas
Novos adjuvantes; Compreensão global dos fatores imunológicos: Assinatura moleculares; Integração entre aspectos imunológicos e não imunológicos. Systems biology 48

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50 It is now possible to select those
antigens that show limited or absent antigenic variability and antibody-mediated protection. This approach to vaccine discovery starts with the analysis of the information in silico  ‘reverse vaccinology’

51 É possível obter as novas vacinas?
O insucesso das vacinas e a preservação da espécie. Sucesso contra enfermidades que matam antes da idade reprodutiva.

52 Figure 1 Role of maternal serum and milk
antibodies (Ab) in protecting offspring. Maternal antibodies transferred (via placenta) protect offspring and attenuate systemic infections during the first 6–12 months after birth. Early (i) or late (ii) weaning influences attenuation of gastrointestinal infection. (i) Western countries (ii) developing countries (B) If there are no specific antibodies in maternal serum this protection is absent. In partsA and B, note that the offspring’s antibodies start to be produced slowly within the first weeks after birth but provide effective protection only at 3–6 months of age; during this time active vaccination will enhance generation of specific antibodies by offspring. Zinkernagel 2003

53 É possível obter as novas vacinas?
Vacina contra-infecção vs Vacina contra-doença