A re­cent US study found that the risk of get­ting hos­pi­talised for other in­fec­tions was halved among chil­dren who had a live ver­sus a non-live vac­cine


Ameasles vac­cine pro­tects against measles in­fec­tion. By in­tro­duc­ing a bit of weak­ened virus, the im­mune sys­tem learns how to deal with it, so when a real measles virus comes along, it can elim­i­nate it. But does the im­mune sys­tem learn more from the vac­cine? Re­cent re­search sug­gests, rather in­trigu­ingly, that it does.

OUR GROUP IRST NO­TICED THIS Phe­nom­e­non in Guinea-bis­sau in West Africa over 30 years ago. We fol­lowed a large sam­ple of the pop­u­la­tion, with reg­u­lar home vis­its. The fo­cus was on nutri­tional sta­tus, but as a ser­vice to the com­mu­nity, in De­cem­ber 1979, we pro­vided a measles vac­cine for all chil­dren. The fol­low­ing year, we ob­served some­thing amaz­ing: the measles vac­cine re­duced over­all mor­tal­ity by more than 70 per cent — much more than could be ex­plained by the pre­ven­tion of measles in­fec­tion, which only caused around 10-15 per cent of all deaths at that time.

Dur­ing fur­ther re­search, it be­came clear that the ef­fect of these vac­cines on over­all health couldn’t be ex­plained BY THEIR DIS­EASE-SPECIIC EF­FECTS. VAC­cines also af­fect the risk of other in­fec­tions. We coined these ef­fects THE “NON-SPECIIC EF­FECTS” OF VAC­CINE.

There are two ma­jor types of vac­cines, live and non-live. Live vac­cines con­tain the dis­ease or­gan­ism in a weak­ened form. They cre­ate a mild nat­u­ral in­fec­tion in the body, usu­ally so mild that there are no symp­toms. These vac­cines give good pro­tec­tion against the dis­ease they were de­signed FOR FROM THE IRST DOSE. (THOUGH THESE vac­cines have the very rare po­ten­tial to cause real dis­ease, par­tic­u­larly in peo­ple with com­pro­mised im­mune sys­tems.)

Non-live vac­cines con­tain the killed dis­ease or­gan­ism or parts of it. They are not very good at stim­u­lat­ing the im­mune sys­tem and usu­ally have to be given with a helper sub­stance, known as an “ad­ju­vant”, and in sev­eral shots to give dis­ease pro­tec­tion. The non-live vac­cines can never cre­ate the real dis­ease, so most doc­tors pre­fer them over live vac­cines.we have now in­ves­ti­gated four live vac­cines and six non-live vac­cines, in Guinea-bis­sau and other low-in­come coun­tries, as well as in Den­mark. A con­sis­tent pat­tern has emerged.

The live vac­cines re­duce death and dis­ease much more than can be EX­PLAINED BY THE SPECIIC PRO­TEC­TION. But the non-live vac­cines, in spite of pro­tect­ing against the vac­cine dis­ease, are as­so­ci­ated with neg­a­tive ef­fects on health, in­clud­ing death, par­tic­u­larly for girls. Here are two ex­am­ples.

BCG vac­cine is a live vac­cine against tu­ber­cu­lo­sis. It is rec­om­mended at birth in poor coun­tries. But new­borns with low birth weight are nor­mally vac­ci­nated later. We tested the ef­fect of BCG vac­cine on over­all health in this group. We ran­domly al­lo­cated Guinean chil­dren who weighed less than 2.5kg to re­ceive BCG at birth or the usual de­layed BCG.

IN THE IRST MONTH OF LIFE, DEATHS FROM any cause were re­duced by more than a third in chil­dren who re­ceived the vac­cine ver­sus those who didn’t. Chil­dren don’t DIE FROM TU­BER­CU­LO­SIS IN THE IRST MONTH of life. But BCG re­duced their risk of dy­ing from sep­sis and pneu­mo­nia — a PURELY NON-SPECIIC EF­FECT OF BCG, WHICH had noth­ing to do with pro­tec­tion against tu­ber­cu­lo­sis.

In sub-sa­ha­ran Africa, BCG is of­ten given with de­lay. Cur­rently, only around 50 per cent of all chil­dren, ir­re­spec­tive of weight, re­ceive BCG at birth. If our re­sults are cor­rect, it would be pos­si­ble to pre­vent 200,000 ba­bies dy­ing each year sim­ply by mak­ing sure that all chil­dren re­ceived the BCG vac­cine at birth.

Diph­the­ria, tetanus and per­tus­sis (DTP) vac­cine is a non-live vac­cine against three se­ri­ous and po­ten­tially deadly dis­eases. So it has been as­sumed that in­tro­duc­ing it would re­duce over­all mor­tal­ity. But when we tested what had hap­pened when the DTP vac­cine was in­tro­duced in Guinea-bis­sau, we were very sur­prised. In spite of pro­tect­ing against the dis­eases, Dtp-vac­ci­nated CHIL­DREN HAD IVEFOLD HIGHER MOR­TAL­ITY THAN chil­dren who didn’t re­ceive the vac­cine.

WE HAVE RE­PEATED THIS IN­D­ING MANY times. Pro­tec­tion against diph­the­ria, tetanus and per­tus­sis seems to come at a very high price: in­creased risk of dy­ing from other in­fec­tions, such as re­s­pi­ra­tory in­fec­tions, par­tic­u­larly for fe­males. Trans­lated into ab­so­lute num­bers, the re­sults in­di­cate that the use of DTP vac­cine in sub-sa­ha­ran Africa may cost tens of thou­sands of fe­male lives ev­ery year.these are just two ex­am­ples among many stud­ies done by our team. Be­sides BCG, we HAVE FOUND BENE­I­CIAL NON-SPECIIC ef­fects of the live measles, small­pox and oral po­lio vac­cines. And be­sides DTP, we have found neg­a­tive ef­fects in fe­males of the non-live pen­tava­lent vac­cine (which com­bines im­mu­ni­sa­TION AGAINST IVE DIS­EASES), AS WELL AS the in­ac­ti­vated po­lio, hep­ati­tis B and H1N1 INLUENZA VAC­CINES, AND WE ALSO pre­dicted a neg­a­tive ef­fect of the new malaria vac­cine in fe­males.

Not many places have the kind of data needed to con­duct these stud­ies, but other re­search groups are now START­ING TO REPLI­CATE OUR IN­D­INGS IN other poor re­gions of Africa and Asia. The same pat­terns have also been seen in wealthy coun­tries. For in­stance, a re­cent US study found that the risk of get­ting hos­pi­talised for other in­fec­tions was halved among chil­dren who had a live ver­sus a non-live vac­cine.

The World Health Or­gan­i­sa­tion re­cently re­viewed the ev­i­dence for NON-SPECIIC EF­FECTS OF THE LIVE BCG AND measles vac­cine and the non-live DTP vac­cine and con­cluded that BCG and measles-con­tain­ing vac­cines could re­duce over­all mor­tal­ity by more than ex­pected, while higher all-cause mor­tal­ity may be as­so­ci­ated with re­ceipt of DTP.

The im­mune sys­tem has tra­di­tion­ally been di­vided into the in­nate and the adap­tive im­mune sys­tem, with the IN­NATE SEEN AS THE IRST LINE OF DE­FENCE, with no mem­ory of pre­vi­ous pathogens. The adap­tive has been seen as the place where the mem­ory of dis­ease or­gan­isms de­vel­ops, which can be mea­sured in the an­ti­bod­ies the dis­ease cre­ates. The pro­tec­tive ef­fect of vac­cines has largely been as­cribed to the abil­ity to in­duce an­ti­bod­ies.

How­ever, re­cent re­search has taught us that the im­mune sys­tem is more com­plex. The in­nate im­mune sys­tem also learns when ex­posed to a dis­ease or­gan­ism. In a re­cent ex­per­i­ment, we showed that vol­un­teers who re­ceived a BCG vac­cine four weeks be­fore a yel­low fever vac­cine, had much less yel­low fever virus in the blood, and this was be­cause BCG vac­cine trained their in­nate im­mune cells to be­come more vig­i­lant. So we now have ev­i­dence that a vac­cine can change the im­mune re­sponse to sub­se­quent un­re­lated in­fec­tions in hu­mans. This goes a long way TO EX­PLAIN­ING HOW VAC­CINES CAN IN­LU­ENCE other dis­eases and over­all health.

VAC­CINES HAVE BEEN USED FOR CEN­TURIES. So if they have such pro­found ef­fects on the risk of other dis­eases, why didn’t we dis­cover this a long time ago? The short an­swer is that you can’t dis­cover what you’re not look­ing for.

Ev­ery­body has been con­vinced that vac­cines only af­fected the tar­get in­fec­tion, so their ef­fect on other in­fec­tions and over­all health was not stud­ied. So while there are many stud­ies that show that vac­cines have pro­tec­tive ef­fects, there is no data that shows that vac­cines only have pro­tec­tive ef­fects.

It is time to change our per­cep­tion of vac­cines: vac­cines are not merely a PRO­TEC­TIVE TOOL AGAINST A SPECIIC Dis­ease, they af­fect the im­mune sys­tem broadly. In the case of live vac­cines, the im­mune sys­tem is strength­ened. In con­trast, non-live vac­cines seem to have a neg­a­tive ef­fect on the im­mune sys­tem in fe­males.

THE LAT­TER IN­D­ING IS AN OB­VI­OUS CAUSE for con­cern, par­tic­u­larly since it would be un­de­sir­able to stop us­ing, say, the DTP vac­cine, as it pro­tects against three se­vere dis­eases. For­tu­nately, there is some­thing that can be done. It ap­pears that if a live vac­cine is given after a non-live vac­cine, the neg­a­tive ef­fect of the non-live vac­cine may be mit­i­gated. So there is an ur­gent need for stud­ies test­ing dif­fer­ent se­quences of live and non-live vac­cines.

Stud­ies into the over­all health ef­fects of vac­cines are pro­vid­ing new in­sights about the im­mune sys­tem and how it may be trained by vac­cines. Live vac­cines seem to be po­tent im­mune train­ers, and with this new knowl­edge we may be able to re­duce global child mor­tal­ity by more than a mil­lion deaths a year. With smarter use of vac­cines, we may also be able to re­duce dis­ease and im­prove child health in wealthy coun­tries.


A doc­tor holds a sy­ringe as part of the start of the sea­sonal in­fluenza vac­ci­na­tion cam­paign in Nice, France.

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