Porque não temos vacinas contra parasitas?

Manoel Barral-NettoFIOCRUZ-Bahia e FAMEB-UFBA

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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

VacinaçãoVacinação

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.

“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.

“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. Jenner's paper was rejected by the Transactions of The Royal Society, so he published his “Inquiry” privately.

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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.

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.

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.

Revolução da cultura de células 1950-1970

• 1955 - Salk's formalin-treated whole virus vaccine provided protection 1955 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)

Era molecular: 1970-1990• 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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Polio Eradication Progress, 1988 - Polio Eradication Progress, 1988 - 20022002

Certified Polio-free regions (113 countries)

Endemic with wild polio virus ( 7 countries) Source: WHO AFP surveillance databasedata from 192 WHO member states

Not Certified but non-endemic (72 countries)

Slide Date: October 03

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Esquema vacinação 0-6a, US 2007

The Jordan Report, NIAID 2007

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Esquema vacinação 7-18a, US 2007

The Jordan Report, NIAID 2007

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Esquema vacinação adultos, US 2007

The Jordan Report, NIAID 2007

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Vacinas disponíveisVacinas disponíveis

Tipo de vacinaTipo de vacina VírusVírus BactériasBactérias

Organismo Organismo mortomorto

Polio, sarampo, caxumba, Polio, sarampo, caxumba, rubéola, varicela, febre rubéola, varicela, febre

amarelaamarela

Tuberculose, febre Tuberculose, febre tifóidetifóide

Organismo Organismo atenuadoatenuado

Polio, influenza, raiva, Polio, influenza, raiva, Hepatite AHepatite A

Pertussis, febre Pertussis, febre tifóide, cóleratifóide, cólera

SubunidadesSubunidades Hepatite BHepatite B

H. influenzaH. influenza B, B, pertussis, pertussis,

menigococos, menigococos, pneumococos, pneumococos,

febre tifóidefebre tifóide

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Mecanismo da Vacina Mecanismo da Vacina contra a Varíolacontra a Varíola

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Resposta Efetora HumoralResposta Efetora Humoral

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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.

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Proteção Mediada por Proteção Mediada por CélulasCélulas

Resposta imune celular

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Basis for effective Basis for effective vaccinationvaccination

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CD4+ T helper subsets

Comparação entre Comparação entre formulações de vacinasformulações de vacinas

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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.

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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. 3

0

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Immune response to YF-

17D

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

Plasticidade funcional de DCs:Estimulação de diferentes PRRs pode estimular respostas adaptativas distintas.

TLR

Pulendram & Ahmed, 2006

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).

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Rosenberg et al 2004

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Perspectivas em vacinas

• Novos adjuvantes;

• Compreensão global dos fatores imunológicos:Assinatura moleculares;

• Integração entre aspectos imunológicos e não imunológicos.Systems biology

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PRR, TLR agonists

Ag carriers

Immunostimulation

Potential toxicity

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