Porque não temos vacinas
contra parasitas?
Manoel Barral-Netto
FIOCRUZ-Bahia e FAMEB-UFBA
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
Vacinação
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.
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.
O nascimento da imunologia (18751910)
• 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.
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
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.
11
Slide Date: October 03
Polio Eradication Progress, 1988 - 2002
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
Esquema vacinação 0-6a, US 2007
The Jordan Report, NIAID 2007
13
Esquema vacinação 7-18a, US 2007
The Jordan Report, NIAID 2007
14
Esquema vacinação adultos, US 2007
The Jordan Report, NIAID 2007
15
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
Hepatite B
H. influenza B,
pertussis,
menigococos,
pneumococos,
febre tifóide
Subunidades
16
Mecanismo da Vacina
contra a Varíola
17
Resposta Efetora Humoral
18
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
Proteção Mediada por
Células
20
Resposta imune celular
22
Basis for effective vaccination
CD4+ T helper subsets
24
Comparação entre
formulações de vacinas
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.
29
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
Immune
response
to YF17D
31
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).
Rosenberg et al 2004
35
Perspectivas em vacinas
• Novos adjuvantes;
• Compreensão global dos fatores
imunológicos:
Assinatura moleculares;
• Integração entre aspectos imunológicos e
não imunológicos.
Systems biology
36
37
39
40
PAMP AND AG PARTICULATE CODELIVERY: THE PERFECT MIX
Ag carriers
4 3
7
9 2
Polymeric Mineral
Liposomes particles
salts,
alum
Emulsion
s
AG
+
PAMP
ISCOMS,
virosomes,
virus-like
particles
THREE COMPONENT VACCINE MODEL
PRR, TLR
agonists
Immunostimulation
Potential toxicity
AG + adjuvant
Protein, peptides,
DNA, RNA
Any substance or
strategy that augments
the immune response
against an Ag
•PAMPs
•Polymeric particles
•Liposomes
ADJUVANT A
ADJUVANT B
•Emulsions (MF59)
•Mineral salts: Alum
Signal O
Signal 1
MHC II
APC
TCR
Th cell
B7 CD28
Signal 2
•Cytokines
ADJUVANT C
•CD40L
Perspectivas em vacinas
• Novos adjuvantes;
• Compreensão global dos fatores
imunológicos:
Assinatura moleculares;
• Integração entre aspectos imunológicos e
não imunológicos.
Systems biology
45
Innate correlates of yF‐17D immunogenicity
identified by systems biological approaches
46
Predictive signatures of gene expression
for vaccines
47
Perspectivas em vacinas
• Novos adjuvantes;
• Compreensão global dos fatores
imunológicos:
Assinatura moleculares;
• Integração entre aspectos imunológicos e
não imunológicos.
Systems biology
48
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’
É possível obter as novas
vacinas?
O insucesso das vacinas e a preservação
da espécie.
Sucesso contra enfermidades que matam
antes da idade reprodutiva.
51
Figure 1 Role of maternal serum and milk
antibodies (Ab) in protecting offspring.
(A) 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
É possível obter as novas
vacinas?
Vacina contra-infecção
vs
Vacina contra-doença
53