Intended for healthcare professionals


Only 12% of Germans say they will have H1N1 vaccine after row blows up over safety of adjuvants

BMJ 2009; 339 doi: (Published 21 October 2009) Cite this as: BMJ 2009;339:b4335

Cell-mediated immunity neglected in influenza vaccination strategies

A previous comment from October refers to natural immunity by
infection, among other things. I and my wife Dr Ann-Cathrin Engwall (born
Svensson) (PhD molecular cell biology with experience from Paul Erlich
Institute, Uppsala University, vaccine development etc) have studied this
subject lately.

During the early stages of the swine flu pandemic in Sweden late this
past summer I observed through the statistics that elderly seemed to be
better protected here as well as in many other countries that were earlier
affected by the swine flu.
My wife, PhD in molecular cell biology and well educated and experiencied
in immunology and virology, at that time wrote a swedish article about the
neglected risk of a potentially suboptimal strategy when Sweden planned to
vaccinate our whole population against the swine flu virus A/H1N1.
The reason for the critizism of this strategy, which I agreed upon, was
mainly that the swine flu was very mild, well spread but very few dead, so
far in the world and also here in Sweden.

Furthermore, in our case the vaccination campaign might cause more
damage than it prevents, since through vaccination if it is successful you
simultaneously most likely prevent the swine flu virus from infecting the
cells and thus inhibiting the generating of a broad cell-mediated T-cell
response, especially CD8+, which could be more useful in the the near

The broadness of this immunity response, she claimed in august 2009,
must come from internal swine flu virus proteins and their many different
epitopes of the MOC I presentation on the surface of the infected cells.
Now if there would be a second wave of the swine flu pandemic - more
pathogenic than the first one - there could be a non-neglectable risk for
the current wave one vaccine Pandemrix to work poorly against the wave two
virus due to possible mutation or mutations of the surface proteins of the
virus that could in fact be one of the reasons for a second wave to be

There is theoretical study that deals with a similar situation

"Our results indicate that avoiding a second influenza epidemic is
plausible given sufficient levels of cross-protection are attained via
natural infection during an early (herald) wave of infection or
vaccination campaigns prior to a second wave. Furthermore, interventions
aimed at mitigating the first pandemic wave may be counterproductive by
increasing the chances of a second wave of infection that could
potentially be more virulent than the first."

You can conclude that natural immunization by the influenza A subtype
itself in some cases can prove to be an advantage in the short term future
compared to a immunization by vaccination which normally only can address
the surface proteins HA and NA.

However this discussed cell-mediated partially protective MOC I CD8+
response may also be similarly useful under other circumstances i.e. in a
more long term view.

In this study


they examine the responses to a common influenza virus and two reassortant
strains of the Spanish flu 1918 H1N1 virus, each containing HA and NA
surface antigens which are closely linked to that strain's potent
virulence. The effects of these strains was compared with those of a 2004
Vietnam isolate of the Highly Pathogenic Avian Influenza (HPAI) H5N1.
Unlike the seasonal flu which poses the greatest threat to very young,
very old and those with immunity weaknesses, the Spanish flu severely
affected especially rather young healthy adults supposed to be strong.
In the case of the highly pathological avian H5N1-subtype virus,
statistics of human deaths reveal a similar trend where the elderly seem
better protected.

The natural cell-mediated response is generated with a MHC I based
presentation of peptides not only from the HA and NA surface proteins but
also from the internal proteins which often are more conserved, e.g. due
to less evolutionary pressure to change/mutate since the cell-mediated
response allows the virus to infect cells often leading to some further
spreading of the virus to other people and due to that a internal changes
might hurt the function of the virus or its interaction with the host
cell. If on the other hand such a mutation hurts the host more, the host
could die more rapidly and thus could reduce the likelihood of infecting
other people. Therefore the conservation of internal proteins should be
supported by natural selection to a higher degree than surface proteins HA
and NA.

Thus there is a logical possibility for completely different subtypes
of influenza A to have some internal proteins in common. Now look at this
article (with Peter C Doherty, the 1996 Nobel prize winner in

Among other things discussed they "primed mice with the H1N1 PR8
strain and the H3N2 X31 strain followed by a challenge with
A/Vietnam/1203/2004, one of the most lethal H5N1 viruses, which causes
severe pathologic changes, even in ducks. While 9 of 10 naive mice died, 9
of 10 primed mice survived past day 10 of infectious challenge and
recovered substantial weight (Figure). The fact that both groups lost
weight indicated protection was occurring by delayed cell-mediated
responses, rather than by the "immediate" cross-protective antibody

So mice could get a highly protective effect against an otherwise
lethal H5N1 strain, most likely from the cell-mediated MOC I CD8+ based
response to conserved epitopes of internal proteins.

This suggests there is a high probability that the protection elderly
humans seem to have against the highly pathogenic avian flu of subtype
H5N1 is at least to some extent derived from the higher historic influenza
exposure elderly people on a probability base have gone through in their

My wife and I late last summer realized that the cell-mediated
protection had the potential to explain what we found and why it not only
was very valuble for elderly people in the swine flu pandemic, but could
be valuble in the future for all those now infected by the relatively mild
swine flu. In Sweden the death rate in the swine flu is very low, with
just around 15 dead so far with nearly all from the high risk groups which
every one think should have been vaccinated anyhow.

Now just recently in October a new study presented further
theoretical and experimental evidence or proof for the existance of the,
in our view potentially vitaly important cell-mediated MOC I and CD8+
based partial human protection against different subtypes of influenza A
that is generated by earlier occasions of natural immunization through any
other influenza or influenzas of any subtype as long as there is a
sufficient conservation of epitopes from internal proteins.

Some implications for the populations and on vaccination strategies :

Nothing so far points against our conclusion that the cell-mediated
protection is clearly neglected today in some influenza vaccination
strategies. A person let say 15 years old and who never has catched the
flu, either because of "good luck" or yearly vaccination against seasonal
flu, could be extremely vulnerable to a highly virulent avian H5N1
pandemic influenza virus with a high risk for death if there is no new
effective vaccine available.

I have a also a new hypothezis that the extremely high number of
swine flu related reported deaths in e.g. the USA, around 7 times more
than the reported world average per capita at this point, may to some
significant degree be explained by the extremely wide spread vaccination
programmes against seasonal flu, especially if they ar directed to very
young people. CDC recommend yearly vaccination for seasonal influenza in
the USA for +6 mån - 18 year old and 50+.
There is a risk younger age groups indirectely get partially deprived of
natural cell-mediated protection against future pathogenic pandemic
influenza A viruses. Even the on the average rather mild swin flu affects
USA severely at this very moment, while countries like Sweden, Germany,
Portugal etc seems rather unaffected as in terms of deaths so far, but not
in terms of number of affected, thus suggesting an indication of a better
immune response through the type of cell-mediated protection discussed

Sweden though with our first time experiment of mass vaccination of
the whole population may be at a higher risk in the future than before,
with our new experiment or strategical effort to deprive or reduce the
chance for the individuals of the population to undergo the broader cell-
mediated natural immunization process associated with catching a mild flu
and generated by the epitopes from the internal proteins of the swine flu

On the other hand both young and old who have gone through a seasonal
flu or two or another pandemic influenza, will have the very valuble
advantage of having a naturally generated cellmediated protection which
will be partially effective against e.g. the avian flu virus if a
sufficient number of nucleoproteins of the avian flu virus are recognised
by the cell-mediated protective immune systeme through its memory of the
nucleoproteins from all earlier influenzas they have gone through. In any
past pandemic influenza as far as is known, which is the only case where
elderly have an empirical influenza protective advantage, we see the
empirical evidence for this advantage repeated but we now also know the
obvious logical immunological explanation for it, thanks to the new
scientific studies.

Thus you can conclude, that with a high probability there is a
significant protective factor of having been naturally immunized by
influenza A subtype viruses before you are exposed to a another subtype
which might be highly pathogenic such as a potential pandemic avian H5N1-

Furthermore there is not only an advantage with vaccination against mild
influenza subtype A viruses, especially for young healthy persons, if you
consider the thereby associated elimination of the advantage of a broader
protective natural immunization process which could otherwise have

Influenza vaccination is most effective for high risk groups and
probably should be more carefully used for most of the population. There
is an american study that found "During the period from 1989 to 1997 the
vaccination rate for people aged over 65 in the US increased from 30 to 67
per cent. Despite this increase, mortality and hospitalisation rates
continued to increase rather than decline as would be expected if the
vaccine was optimally effective."


Maximal vaccination rate is not always the optimal rate...

Competing interests:
None declared

Competing interests: No competing interests

01 December 2009
Bo A Engwall
Independant analysist