Saudades de viajar...
Segunda-feira, Janeiro 31, 2011
Saudades de viajar...
Quinta-feira, Janeiro 20, 2011
Recentemente tenho trocado mensagens com um amigo sobre a questão de vacinações infantis, particularmente nos primeiros meses de vida do bebê. Este amigo se diz preocupado com a quantidade de vacinas dadas a crianças tão jovens, aparentemente convencido pelos argumentos - falaciosos - do tipo "too many, too soon". Não o culpo, o movimento anti-vacinação tende a ser bom em propaganda na exata proporção em que são ruins em ciência, e para muitos pais as táticas de amedrontamento utilizadas por picaretas deste tipo podem ser bastante convincentes.
De qualquer forma, achei que seria interessante compartilhar com vocês esta discussão. Está em inglês, mas tenho certeza que meus cultos, distintos e praticamente inexistentes leitores não se importarão.
A discussão toda começou quando coloquei a seguinte imagem no meu perfil do Facebook:
A discussão que se seguiu é reproduzida abaixo, na íntegra (reduzi os links para não avacalhar o layout do blog):
05/01/2011, JH: Nice,relevant.... hmm what age would you vaccinate your child at?
05/01/2011, Felipe Campelo: Since I am no doctor, I will follow the guidelines from the Brazilian Ministry of Health. Each country has its own vaccination schedule (which tends to be pretty similar for most of Europe and the Americas), but it usually starts at around 2 or 3-months of age. There are good reasons for this, as explained in the NHS page on immunisation:
For the UK schedule, take a look at:
05/01/2011, JH: What if i told you Americans (USA) dont vaccinate children under the age of 6 months. Would you question why there is a variation between countries (even though you are not a doctor)?
05/01/2011, Felipe Campelo: I would say that at least one vaccine (Hep B) is recommended on the U.S. starting on the first month of life, and while others are recommended after the sixth month, the minimum vaccination age there is pretty much in line with the NHS:
Regarding the differences on vaccination schedules between countries, I suppose they are more a function of policy and public acceptance than of the science behind it, particularly because the ages in one country tend to fall within the recommended range of the other.
How about you, why do you think there are such differences?
06/01/2011, RCL: A lot of whatever is policy regulated is done with critical detachment from the science that matters...its everywhere...even in fields such a health, where one would think things are regulated with a certain imperative to generate a state of certainty.
17/01/2011, Felipe Campelo: Updated U.S. vaccination schedule (2010):
Also, check the http://www.immunizenow.org/ website, you can find lots of links there. About your concerns on the age of immunization, they looked a bit like those made on the "Too many, too soon" front. You can find some info about that on:
18/01/2011, JH: My main problem is the apparent weakness in establishing an upper limit in terms of the number simultaneous vaccinations an under 6 month old child can cope with. The papers I have found all reference the following paper, which claims a child could handle 10 000 simulataneous vectors, but does so using an order of magnitude analysis. Any comments on the "DO VACCINES "OVERWHELM" THE IMMUNE SYSTEM?" section?
Addressing Parents’ Concerns: Do Multiple Vaccines Overwhelm or Weaken the Infant’s Immune System? PEDIATRICS Vol. 109 No. 1 January 2002, pp. 124-129
20/01/2011, Felipe Campelo: The main thing is, babies - and people in general - are exposed to antigens *all the time*. Every time a baby takes her hand (or anything) to her mouth, every breath she takes, every time she feeds, she's presenting her immune system with hundreds or thousands of antigens - and that's a good thing, because the protection she gets from the mother's antibodies (acquired by breastfeeding) doesn't last very long, and she needs to prime her adaptive immune system with the most common antigens found in her environment.
While the delivery system of a vaccine is more dramatic - we're all nervous at the sight of a needle - the antigens present in the shot are no different to the immune system than any other antigen - all the B-cells see are protein patterns, no matter the origin. And there's really no way on Earth that a dozen "extra" antigens would make any difference in terms of overwhelming an immune system that is already dealing very successfully with a few thousand antigens every day.
One can even argue that vaccination is a lot safer than any other form of antigen presentation: unlike the stuff present in the local environment of the baby (no matter how clean it is), vaccine ingredients are all known and tested for safety, the antigen itself is composed of fragments of dead, or at least very attenuated microorganisms (which can't provoke the disease), etc.
Regarding the paper on "Pediatrics", I agree with you that doing an order-of-magnitude analysis means looking at the "best-case scenario" - and we engineers hate best-case analyses! But in any case, even if they are wrong by three orders of magnitude, one would still be pretty safe with 10 vectors at once. And that's not even what happens! The early childhood vaccination schedule recommends about 10 vectors over the first 6 months of life - which leaves plenty of time for the immune system to mount the immune response, acquire memory of the antigens presented, and get back to normal serum levels of antibodies.
For a quick look at an immune response curve: http://goo.gl/jpYhI
For more information, I find Ivan Roitt's "Essential Immunology" quite useful. It's a textbook on the topic, so it can get rather technical at times, but I find it easier to read than the other one I have here (Maurice Gorman's "Handbook of Human Immunology").
Oh, and here are links to two articles I find quite interesting:
Felipe "hug me, I'm vaccinated" Campelo
20/01/2011, JH: @Campelo. Hi man, I was looking forward to your reply and you didn't disappoint. ;).
I was happy you could see my objections to basing policy on order of magnitude analysis.
From the paper; for reference:
"A more practical way to determine the diversity of the immune response would be to estimate the number of vaccines to which a child could respond at one time. If we assume that
1) approximately 10 ng/mL of antibody is likely to be an effective concentration of antibody per epitope (an immunologically distinct region of a protein or polysaccharide)
2) generation of 10 ng/mL requires approximately 10e3 B-cells per mL)
3) a single B-cell clone takes about 1 week to reach the 10e3 progeny B-cells required to secrete 10 ng/mL of antibody (therefore, vaccine-epitope-specific immune responses found about 1 week after immunization can be generated initially from a single B-cell clone per mL),
4) each vaccine contains approximately 100 antigens and 10 epitopes per antigen (ie, 10e3 epitopes), and
5) approximately 10e7 B cells are present per mL of circulating blood, then each infant would have the theoretical capacity to respond to about 10 000 vaccines at any one time (obtained by dividing 10e7 B cells per mL by 10e3 epitopes per vaccine)."
So are they saying that in theory due to the number of naive(?) B cells and Helper T cells in 1 ml of blood, given a week of doing nothing else, the B cells will produce sufficient antibodies for 10 000 distinct non replicating vaccines each containing 1000 epitopes? Find me simulation/experimental validification please...
21/01/2011, GM: Interessante. Não sou engenheiro mas darei meu palpite de biólogo anti vacinas em excesso. Faltou citar o pior problema de vacinações "desnecessárias" - chance de doenças autoimunes e reversão ao fenótipo selvagem de vacinas atenuadas.
21/01/2011, Felipe Campelo: Permita-me então oferecer uma perspectiva diferente aos seus palpites de biólogo:
1) Doenças auto-imunes (DAIs): Suponho que você esteja se referindo à Síndrome de Guillain–Barré - que normalmente é a reação auto-imune mais citada (http://goo.gl/j5589 ; http://goo.gl/db0WP) e outras do gênero. Neste caso, é preciso considerar algumas coisas ao se utilizar este argumento: por um lado, deve-se considerar a taxa de ocorrência destas doenças associadas à vacinação, e suas potenciais consequências; por outro, a gravidade da doença prevenida pela vacina, e sua probabilidade de ocorrência. A evidência que consegui encontrar sugere que a indução de DAIs por efeitos de vacinas é extremamente rara, muito inferior a taxas de ocorrência decorrentes das doenças que a vacina previniria (ver http://goo.gl/zuV22 ; http://goo.gl/bCtsi para estudos relativos a influenza, e references therein para outros estudos). Meu ponto neste caso é: os ganhos superam demais os riscos, a menos que a doença seja extremamente rara ou extremamente branda. Um review bacana do tema pode ser encontrado em http://goo.gl/5WVtu.
2) Reversão ao fenótipo selvagem de vacinas atenuadas: neste caso, acredito que o único exemplo que eu conheça seja o do vírus da polio na Nigéria, cuja descendentes da cepa da vacina andam infectando gente. Neste caso específico, o problema ocorreu por uma conjunção de fatores: uma população com grande incidência de imunodeprimidos, e com taxa de vacinação muito abaixo do necessário para se obter imunidade de grupo. Um comentário bacana sobre este caso pode ser encontrado aqui: http://goo.gl/usiy9
De qualquer forma, este segundo problema tem que ser considerado na mesma luz do primeiro: chance de dar merda e intensidade da mesma X benefícios. Confesso não ter tanta informação assim sobre este tipo de problema, então se você puder dar uma esclarecida (em relação a riscos de ocorrência, etc) eu ficaria bastante agradecido.
Voltando ao ponto original do post, entretanto, perceba que o que foi discutido não é a vacinação excessiva, mas sim a vacinação infantil de acordo com o calendário utilizado na maioria dos países. Para este caso, não tenho certeza se as suas duas ressalvas se aplicam - as doenças prevenidas são diversas ordens de magnitude mais sérias e mais prováveis que quaisquer possíveis complicações.
25/01/2011, JPH:ok.... Here is support for the "too soon" hypothesis being correct.
"Immune immaturity affects infant antibody responses in spite of the repeat administration of multiple vaccine doses at a few weeks intervals. Antibody responses to three doses of tetanus–diphtheria–pertussis or Hib conjugate vaccines are lower following a 2–3–4 than a 2–4–6 or 3–5–12 months schedule [18,19]. Using the rapid schedules, a greater proportion of infants fail to respond to relatively weak vaccine antigens, such as diphtheria toxoid [18,19]. In Sweden, a lower overall risk of pertussis disease was measured when the third dose was delayed in the second year of life (i.e. following a 3–5–12 versus a 2–4–6 months schedule ." - Siegrist,CA., Neonatal and early life vaccinology Vaccine 19 (2001) 3331–3346
Balls in your court. ;)
31/01/2011, Felipe Campelo: I have been looking at this in what little spare time I have, and so far I've come across a number of studies (some of them cite the 2001 paper you mentioned) that do not necessarily agree with the statement above. For instance:
"Our understanding of neonatal immunity has developed in a step-wise manner. Initial assumptions were that neonates were immature or immunodeficient. This supposition was replaced by the idea that neonates are immunodeviant. Subsequently, demonstrations that neonates are competent to mount mature responses raised the possibility that simply smaller size or immune-cell numbers could account fully for the differences between neonates and adults. However, it is becoming increasingly clear that both human and mouse neonates mount various responses, ranging from deficient or deviant to fully mature, depending on the conditions of antigen exposure. This flexibility of responsiveness might have important functions in protecting the developing organism from potentially dangerous inflammatory situations, at the same time as providing protection against potentially life-threatening infections (Box 2)." - (Nature Reviews Immunology - http://goo.gl/LmxJU)
"The classical paradigm that newborns have incompetent T lymphocytes developing only weak or even tolerogenic responses should clearly be reconsidered. The observation that mature cellular immune responses can be developed in early life suggests that under appropriate conditions of stimulation neonatal T lymphocytes can be
instructed to ﬁght intracellular pathogens (Fig. 1). We can therefore hope that the identiﬁcation of molecular pathways leading to DC and T cell activation in human neonates will lead to the development of new vaccines eliciting efﬁcient and safe protective responses against these agents early after birth." - (Clinical and Experimental Immunology - http://goo.gl/83yub)
Other works presented conclusions that accelerated vaccination schedules could have an even higher effectiveness for some vaccines, e.g.:
"an accelerated vaccination course against HBV (three doses at 10 day intervals) elicited protective levels of anti-HBs antibodies more rapidly than a classic course (three doses at zero, one, and 6 months) and without a difference in the rate of seroprotection after 1 year." - (Pediatrics International - http://goo.gl/Gu9o3)
The thing is, one paper does not a medical discovery make: replication and improvement are an essential part of of science in general (and specially of medical science). One must take a look into the literature as a whole, to see where the consensus of evidence is building. I am still searching for a comprehensive review or meta-analysis of the data, but haven't had much time to dig this stuff. In any case, the "too many" part of the hypothesis does not seem to hold much water (even if we discard the order of magnitude analysis of that previous paper, the immunology is pretty clear on the subject - see, e.g., http://goo.gl/0s0Il ; http://goo.gl/INBdM; http://goo.gl/xl4uH). The "too soon" could be partially true for some vaccines (if you interpret it as "sooner than optimal"), and partially false for others (if you follow the same interpretation), but I don't think either the lower or the upper ends of the recommended vaccination age are out of the confidence interval for optimality.
In any case, I personally think it is pointless (and kind of arrogant) for me to try to outthink the whole medical research community in their field of expertise - these guys make a living out of studying this stuff, and tend to be pretty good it. I have contacted two of the authors of the Science-Based Medicine collaboration (http://www.sciencebasedmedicine.org/) who are also practicing physicians and researchers (http://goo.gl/rMUeb ; http://goo.gl/ftbxV), and asked if they could kindly point to relevant technical literature on the subject. I'll let you know when I get more info.
Cheers from a father-to-be (coming August - yeeeah :-D )