Monday, 21 January 2002
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POST 00415E : FREEZING AND VACCINE EFFICACY

Follow-up to Posts 00402E, 00406E and 00407E

21 January 2002
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Anthony Battersby is concerned about
sero-conversion studies to see if frozen vaccines work and wonders how one
would set about doing it. It seems to him that it would be unethical to
knowingly use frozen vaccines. And if it were found that sero-conversion
was inadequate, how would we know that it was due to the vaccine having
been frozen or some other factors. Frozen vaccines may still be potent, he
adds, but what are the effect of injecting a vaccine with large particles
in it. He is not really clear where this suggestion is supposed to lead and
wonders if after all these years and all the manufacturers' advice, it is
being seriously suggested that frozen vaccine does not matter?

He has recently been in a country where reaction to unfrozen DPT (which is
normal) was cited as a reason why parents will not allow their children to
have two injections at the same time. He imagines that the reaction from
lumpy DPT is likely to be greater than the one from homogeneous DPT.

Hans Everts disagrees with the moderator's
comments in Post 00406E. There is plenty of evidence, he says, that
freezing damages the vaccine and changes its morphology. There is very
little evidence what the impact is on the immune response. It is surprising
to read that "refined knowledge about vaccine efficacy after freezing
wouldn't serve any useful operational purpose". The options to prevent
freezing range from using eutectics, taking vaccine out of the cold chain,
using icepacks with cooled water and changing equipment specifications, all
of which have very serious operational consequences.

Before recommending changes of cold chain practices at a large scale, we
must be certain the risks are worth it. If the changes are in line with
what we think the future cold chain looks like or should look like -
simplified and with vaccine out of the cold chain - there is of course no
objection. But if the changes actually lead to operational and logistics
complications or to unaffordable equipment because of refined
specifications, then we better be sure they are absolutely necessary.

The whole cold chain is based on the fact that a certain loss of potency
due to heat exposure is acceptable. That is the basis of the VVM. Hans
fully realizes that freezing differs from heat exposure in that it leads to
a change in the physical state of the vaccine. The question is if this
qualitative leap in the physical state implies the same qualitative leap
for the immune response from fully immunogenetic to not at all
immunogenetic, or is there a margin. Freezing at -3°C does not have the
same effect as at
-20°C. Can we afford to ignore this? The former is what we are talking
about, related to the current cold chain. The latter implies storage in
freezers and is a different issue.
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Moderator's comments

First let me make a clarification on one point in Post 00412E. The
statement on WHO recommendation that reconstituted vaccines be kept on ice
was obviously partial and in the context of Anthony Battersby's comments.
The primary objective of keeping these vaccines on ice is to protect their
potency. But when they have been inadvertently contaminated, keeping them
on ice will also slow down the development of the contaminating organism.

I share some of Anthony's concerns, not as much for research protocols as
for operational implications. This is the basis of Hans' disagreement, I
believe. We can all draw our own conclusions from James Cheynes' literature
review (Post 00406E). There is a general consensus on the
physical/mechanical damage inflicted to vaccines by freezing. However, the
five references quoted by James also indicate loss of potency but questions
remain about the effect on "protective efficacy". For example in "Vaccine",
it is said that there is damage "to immunogenicity of pertussis vaccine
...but that further study is required to determine the effect....on vaccine
efficacy".

I would then ask the question "Can potency/immunogenicity be damaged
without damage to efficacy?" Only one reference quotes a study of the
efficacy of frozen tetanus toxoid in vivo on human volunteers. Even if it
is said that all persons immunized acquired a protective level of tetanus
antitoxin, these "persons" were young military recruits whom I view as the
healthiest individuals. Can we infer from this statement that often-sick,
often-poorly malnourished children in the developing world will have the
same immunological response to a damaged vaccine? I believe that the immune
system of such children is weakened.

I agree with Hans that freezing at -3°C probably does not have the same
effect as at -20°C and that the loss of immunogeniticity is likely gradual.
But I meant "operational purpose" only in the hypothesis that there would
be no damage to potency whatsoever. Nowhere in the industrialized world, as
far as I know, a frozen vaccine with any loss of potency would be used,
even a minimal loss. Can you imagine the scandal? The Minister of Health
would have to resign in no time at all. I then ask the question "Can we
have different moral and ethical standards for children in the developing
world?" And if we do find that there is no damage to potency, the loop is
complete and we are back to Anthony's question "after all these years and
all the manufacturers' advice, it is being seriously suggested that frozen
vaccine does not matter?"

I also fully agree with Hans about operational implications of all the
options to prevent freezing. But these are upstream implications and I was
referring to downstream ones after freezing has occurred.
______________________________________________________________________________

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