The Global Alliance for Vaccines and Immunization—a millennial challenge

[Guest guest]

Love the title of the publication - Nature????? Anything but. The usual

smallpox lies.

Sheri

http://www.nature.com/cgi-taf/DynaPage.taf?file=3D/ni/journal/v1/n1/full/ni0=

70

0_5_fs.html & _UserReference=3DC0A804EC4651924DB1E23C9D86A13B8CC738

=20

Volume 1 No 1 - July 2000 =20

=20

Commentary

=20

=20

Nature Immunology 1, 5 - 8 (2000) =A9 Nature America, Inc. =20

=20

=20

The Global Alliance for Vaccines and Immunization=97a millennial challenge

Gustav J. V. Nossal=20

Department of Pathology, The University of Melbourne, 3010=

Australia

Global immunization of children is an elusive goal of public health

officials world-wide. Extraordinary recent funding and organizational

initiatives as described by Gustav Nossal have ignited renewed optimism

that the stage is finally set to bring this acheivement within our grasp.=20

If an observer from a distant planet was to achieve the triumph of

intergalactic travel, she would find much to amaze her on spaceship Earth.

In particular, why have the six billion individuals with the most developed

brains not learnt to live in greater harmony with one another? The question

will also preoccupy most readers of this highly welcome new journal. These

readers hold in their hands history's most cost-effective public health

tools: the precious legacy of Jenner and Louis Pasteur. Indeed, it

could be argued that access to life-saving vaccines is one of the basic

human rights of the child. Striving to bring vaccines, including newer

ones, to every one of the 135 million or so infants born each year

constitutes a moral imperative.M. Hilleman

=20

Jenner

=20

Human effort usually falls far short of the ideals that inspired it. On

this occasion, however, a confluence of circumstances suggests the

possibility of an exception. The world has made a new beginning in the

field of global immunization. At the dawn of the new millennium, a

challenge known as the Global Alliance for Vaccines and Immunization (GAVI)

has been laid down. The purpose of this brief article is to describe its

origins and purpose.

Historical aspects

In many respects, this story begins with the glorious achievement of

smallpox eradication1. Although it took 180 years from Jenner's original

breakthrough to the final result, the World Health Organization's (WHO)

smallpox eradication campaign itself=97the planned and coordinated

determination to treat the world as a single entity=97actually took only 11

years to complete. Apart from the two million or more lives saved each

year, and the countless further lives spared the horror of dreadful

scarring, smallpox eradication showed the power both of the vaccine

approach and of coordinated global action. Emboldened by this success, the

WHO embarked on the Expanded Program on Immunization (EPI) aiming to bring

six common childhood vaccines (diphtheria, pertussis, tetanus,

poliomyelitis, measles and BCG) to all the world's children. Largely due to

resource constraints EPI got off to a slow start until in 1984 an historic

meeting was held in Bellagio, the delegates of which included

representatives of such prominent organizations as WHO, United Nations

Children's Fund (UNICEF) and The World Bank. These key organizations

embraced the concept of universal childhood immunization, leading to the

unlocking of approximately US$100 million per year, via UNICEF, for EPI. As

the program took off, immunization rates in the developing countries rose

rapidly from around 5% of the birth cohort to around 80%. Although it must

be admitted that not all 80% were fully immunized, it is estimated that

this effort has saved 2=963 million lives each year.M. Hilleman

=20

Louis Pasteur

=20

So impressed was the World Health Assembly by the power of this approach

that the decision was taken to embark on a global program of polio

eradication. It was soon realized that routine infant immunization alone,

even with relatively high coverage rates, would not achieve this goal.

Accordingly, three further strategies were brought into operation.

The first was the introduction of regular National Immunization Days (NIDs)

where, following extensive media publicity and social mobilization, all

children aged under five in a particular country were given the oral polio

vaccine regardless of previous immunization history. Secondly, in most

cases, two NIDs were held a month apart and the program was continued for

three years or more. This meant the program reached millions of infants who

had previously escaped the routine immunization net and it produced a

certain degree of herd immunity so that chains of transmission were broken.

NIDs alone, however, would not have sufficed without the third strategy:

extensive surveillance and accurate laboratory diagnosis. Intensive

searches for cases of acute flaccid paralysis that may have been caused by

polio were carried out. Two stool samples were taken from each patient and

examined by trained laboratory personnel in order to diagnose the last few

polio cases, distinguishing them from patients suffering from other causes

of paralysis. Armed with this information, the final phase could

begin=97namely mop-up immunization campaigns. These were resource and

personnel-intensive programs where immunization teams actually brought the

vaccine into villages on a dwelling-to-dwelling basis. As a result of this

monumental effort, most parts of the world are now polio-free, and the

concentrated work going on in the Indian subcontinent and sub-Saharan

Africa is progressing rapidly meaning that global eradication may be only

two or three years away.

Many governments, United Nations (UN) agencies and foundations have

contributed to polio eradication, but special mention must be made of

Rotary International. In a splendid grass-roots effort Rotary International

has not only raised US$500 million or more, but has also provided extensive

volunteer labor, especially on NIDs. This great humanitarian work deserves

wider acknowledgement and applause.

The Children's Vaccine Initiative (CVI)

By 1990 some storm clouds had begun to gather over the global immunization

effort. It appeared that 80% coverage constituted some kind of plateau:

despite much effort the global figure did not rise further and indeed in

some countries had started to fall. A degree of donor fatigue had become

apparent and a renewed commitment was required. Thus, at the 1990 World

Summit for Children held in New York, the CVI was born. Initially this had

a heavy research flavor but with the long-term hope of being able to use

modern technologies to minimize the number of infant injections through

simplified vaccine delivery and more combined approaches. However, it soon

became apparent that advocacy and fundraising were also required. To that

end, CVI set up a Consultative Group which united all elements of the

immunization spectrum including UN agencies, bilateral donors, foundations,

industry representatives and developing country experts, and which convened

every two years. These occasions for a global sharing of information proved

most helpful. CVI also did excellent work in socioeconomic analysis,

cost-benefit studies and priority setting. However, CVI did not have

adequate resources to make much of an impact on vaccine research, and in

the realm of advocacy and fundraising, a certain tension between CVI and

WHO became apparent. As a result in late 1993 the then Director of WHO,

Hiroshi Nakajima, made some important decisions. While retaining

independence, WHO and CVI were to have the same Head, J.W. Lee.

Furthermore, they were to be guided by the same Scientific Advisory Group

of Experts (SAGE). I had the honor of being named Chairman of this combined

group. The major remaining problem was a very severe limitation on

resources.UNICEF

=20

Community involvement.

=20

Embryology of a new global approach

The more the work of the SAGE progressed, the more it became apparent that

there was a terrible defect in the global approach. New vaccines of great

power were coming through the research and development pipeline and had

been introduced or were about to be introduced into the immunization

programs of industrialized countries, but there appeared to be no prospect

of these becoming available as part of EPI. The Hemophilus influenzae B

(Hib) vaccine represents a good example of this. This carbohydrate=96protein

conjugate, embodying the principle of T cell=96B cell cooperation, was the

fruit of extensive research within academia and development work within

industry. It was, therefore, considerably more expensive than the common

EPI vaccines especially as expiration of patents and thus increased

competition had driven the prices of the common EPI vaccines used in

developing country to very low levels. The Hib vaccine has been

spectacularly successful throughout the industrialized world, exceeding

even the most optimistic expectations. Through a combination of wide

acceptance by parents and a herd immunity effect, it has led to the virtual

elimination of this common cause of infant meningitis in those countries

where it is used. But it is only quite recently that some of the richer

developing countries have been able to afford to use it. As a matter of

fact, even hepatitis B vaccine=97now available for mass purchase at around U=

S

$0.50 per dose=97is too expensive for many of the countries in which it is

needed.

Three events in 1998 heralded the beginning of a new global approach.

Firstly the WHO appointed a dynamic new director, Gro Harlem Brundtland,

who was determined to make a major mark and to revitalize the organization.

Soon afterwards the President of the World Bank, D. Wolfensohn, in

conjunction with myself as Chairman of SAGE and Feachem as the

Senior Health Officer within the World Bank, convened a Vaccine Summit.

Held at the World Bank, the Summit delegates included Brundtland; Carol

Bellamy, the Executive Director of UNICEF; key industry leaders; senior

academics; and various officials who met to forge a new vaccination

strategy together. And finally, at long last a major new source of finance

was identified. In December of 1998 H. Gates III, and his wife

Melinda French Gates, launched the Bill and Melinda Gates Children's

Vaccine Program with an initial pledge of US$100 million. This proved to be

only the first of many gifts they made, and at the time of writing their

contribution to the immunization program stands at well over US$1 billion

in donations and pledges.

That first World Bank Summit drew attention both to the beckoning

opportunities and to the dimensions of the funding gap, so a working group

drawn from the WHO, UNICEF, the World Bank, the Bill and Melinda Gates

Foundation and the Rockefeller Foundation engaged in an extensive series of

studies and consultations, the results of which were brought back to a

second Summit meeting held in Bellagio in March, 1999 (ref. 2). This

meeting concluded that the CVI should be replaced by a successor body that

was not independent but rather totally dependent on the major sponsors, who

needed to be involved at the highest level=97Chief Executive if possible. It

also created task forces in three important fields: advocacy, financing and

within-country coordination. Shortly afterwards a fourth task force on

research and development was created. Tore Godal, the distinguished

Norwegian immunologist and long-serving Director of the WHO's Special

Program for Research and Training in Tropical Diseases, was recruited as

Coordinating Secretary of the CVI's successor group, which became GAVI. The

new program was ceremonially launched at the World Economic Forum in Davos,

Switzerland, on 31 January 2000. But before describing the mission of GAVI

in detail, it is necessary to say a little more about the Bill and Melinda

Gates Foundation.

The Bill and Melinda Gates Foundation

The Bill and Melinda Gates Foundation is now the largest charitable

foundation in the world=97valued at US$21,800 million. Its two main areas of

concern are information science and health. I have the great honor of

chairing the Strategic Advisory Council of the Bill and Melinda Gates

Children's Vaccine Program, which at the moment has two major arms. The

first, funded to US$100 million, is devoted to the introduction of four

vaccines of global significance (hepatitis B, Hib, Streptococcus pneumoniae

conjugate and rotavirus) and two vaccines of regional significance (yellow

fever and Japanese B encephalitis). An extensive series of disease burden

studies and field trials is under way, aimed at setting priorities and

identifying possible barriers to widespread introduction. The second major

arm is the Malaria Vaccine Initiative (MIV)*. With funding levels of US$50

million, this program has just started. Its main brief will be to bridge

the gap between preclinical research on malaria vaccines =96which has

identified promising candidate antigens and/or new vaccine approaches=97and

the quite different world of clinical trials. Amongst other things, the MVI

will facilitate the manufacture of trial vaccine lots under Good

Manufacturing Practice conditions. It will also help to identify suitable

trial sites and to coordinate clinical studies according to world best

practice protocols.

These two programs are implemented by a non-governmental organization known

as PATH (Program for Appropriate Technology in Health). PATH has extensive

experience in vaccine field trials and has a number of offices in

developing countries. Although the Strategic Advisory Council will

supervise the strategic elements of the program, each subprogram will have

its own technical advisory group comprising of the very best experts in the

world on the particular disease concerned.M. Hilleman

=20

Jet gun administration of vaccine

=20

Other Bill and Melinda Gates Foundation benefactions in the vaccine field

include contributions to the polio eradication campaign, contributions to

the International AIDS Vaccine Initiative and a new tuberculosis vaccine

effort. One particularly imaginative applied research program, currently

financed by the Foundation to the tune of US$40 million, is called Diseases

of the Most Impoverished (DOMI). DOMI is based at the new International

Vaccine Institute in Seoul, Korea, under the directorship of Clemens.

Its work is focussed on diseases such as typhoid, cholera and shigellosis

or bacillary dysentery.

But the largest Bill and Melinda Gates Foundation donation is to the global

Children's Vaccine Fund (CVF): the pledge stands at US$750 million. This is

absolutely central to the GAVI project.

Further mobilization of public and private sectors

The extraordinary generosity of the Bill and Melinda Gates Foundation is

meaningful not only because of the huge sums involved but also because of

the leverage it confers on the CVF. There is no doubt in my mind that it

has helped to galvanize other public and private sector efforts. Two

initiatives are worthy of special mention.

On 2 March 2000 the President of the United States, Bill Clinton, convened

a White House meeting devoted to this program and related aspects of global

health. At this meeting he revealed that he was seeking from Congress not

only a concrete contribution to the CVF, but also tax credits for companies

prepared to invest in this general area and in other aspects of health in

the developing world. Although the details remain to be worked out, we

could be talking about as much as a further US$1 billion.

The President of The World Bank, D. Wolfensohn, stated that he would

be seeking a replenishable fund to the order of US$1 billion, so that the

IDA (a branch of the bank that specializes in soft money loans at

concessional or zero interest) could lend for health purposes, chiefly in

the field of vaccines and drugs.

Although this initiative is also not yet finalized it represents a

magnificent further step forward. It appears certain that the overseas

development aid agencies of industrialized countries will take note of

these developments and will pitch in either to the Global Vaccine Fund or,

more likely, to efforts in particular developing countries of interest to

each donor. To what degree other large foundations or rich individuals will

respond to the challenge remains to be seen. President Clinton has, on a

number of occasions now, called on them to imitate Bill Gates to whatever

degree they find possible.

The position of industry

The pharmaceutical industry, including the major companies involved in

vaccine production, has been party to all of the above discussions and

represented at many meetings either at Chief Executive level or via the

Internal Federation of Pharmaceutical Manufacturers Association (IFPMA). As

a result, some very serious pledges have been made. In summary, industry

wants to help and is prepared to do so. They are prepared to make vaccines

available to developing countries at prices far below those charged in

industrialized countries. However, they would like certain understandable

concerns addressed.

Firstly, they would not wish to see their quite considerable private

markets threatened or undermined in the larger developing countries in

which a substantial middle class already exists. In cases of technology

transfer to vaccine manufacturers in developing countries, they would like

their intellectual property rights to be respected and to have, therefore,

normal joint venture and licensing processes observed. They are concerned

to ensure that every step be taken to avoid contraband or black markets, so

that vaccines intended for the poorest countries and made available at the

lowest prices do not find their way back to richer countries and

undermining the existing markets there.

Most of all, they wish to see the public sector guaranteeing the purchase

of large and defined volumes of vaccines, preferably for a number of years.

This could potentially break the " chicken and egg " situation that currently

exists. (That is, when volumes are low, prices are high, and while prices

remain high, the countries potentially capable of absorbing large volumes

cannot afford to purchase.) As soon as the CVF reaches a sufficient size,

high volume purchases of the newer vaccines could be guaranteed.

Industry has also said it would be prepared to invest in the research and

development of vaccines of interest solely or chiefly to developing

countries and here attention must be given to both " pull " and " push "

mechanisms of incentive. " Pull " would mean promises of purchase. " Push "

might represent public sector involvement in the initial and risky phases

of research and development. This is an area in which one can foresee bold

and sizable developments in the future.

The three-fold mission of GAVI

The imperative priority for GAVI, and the first drain on the CVF, will be

the provision of newer vaccines for the poorest countries of the world.

Hepatitis B and Hib will be in the forefront. Initially the program will be

targeted at countries meeting three criteria: a gross domestic product per

head of population of less than US$1,000; a clear commitment to

immunization (as shown by at least a 50% coverage of the birth cohort with

the six traditional EPI vaccines) and a population of less than 150

million. Of course, it is not the intention that China, India and Indonesia

be denied access to GAVI. Rather, it is believed that the best way of

helping these countries is, initially, to upgrade their existing

substantial indigenous vaccine-manufacturing capability. To that end,

discussions between GAVI and these three countries have already begun.M.

Hilleman

=20

Jenner and the first vaccine trial

=20

About 50 nations=97with a combined birth cohort of about 40 million=97fitted

the three criteria when the program was announced, and it is clear that

this number will increase as countries make plans to improve their

immunization performance. It is highly encouraging that, at the time of

writing, 47 countries have already indicated to GAVI their wish to

participate in the program. But it cannot be stressed sufficiently that

such a program can only succeed if there is a full and effective

partnership between GAVI and the developing country itself. To that end,

each country will be encouraged to create a national immunization

coordinating committee involving the Ministry of Health of the country

concerned, the relevant United Nations agencies, all interested

non-governmental organizations and, where appropriate, one or more

indigenous vaccine manufacturers. The intention is to avoid any semblance

of paternalism in the arrangements and to create a within-country situation

where the programs become so successful that, after an appropriate number

of years, the government itself assumes responsibility for financing them.

As external sources of funding are unlikely to last forever, this is the

only way to ensure long-term sustainability. Since programs will be

tailored to each country's needs, there will be some variation in which

vaccines are added and in what order; decisions will be informed by

continuing research on disease burden and field efficacy.

The CVF will sit within UNICEF but will be supervised by an independent

board. GAVI itself will have a high profile board, initially chaired by

Brundtland, with senior representatives from the other major partners, and

several outside directors of the highest standing. Obviously, GAVI will

have access to scientific and technical expertise from SAGE, the Gates

Strategic Advisory Council and whatever other national or international

expert body it seeks to consult. The aim is not to create a vast new

structure or to introduce costly overlaps. Rather, GAVI represents an

unincorporated and relatively unstructured joint venture between the

committed parties.

The second aim of GAVI will be to repair the deteriorating vaccine

infrastructure in the poorest countries and to ensure the greatest possible

safety of vaccine injections. This will involve rejuvenation of the cold

chain, introduction where possible of auto-disabled single-dose syringes,

and the safe disposal of syringes and needles using suitable packaging with

eventual incineration. The issue of safe injection is of paramount

importance in countries where unauthorized re-use of syringes and needles

is common, and where HIV and hepatitis B and C are present in substantial

numbers of people. It turns out that the extra costs of disposable

injection equipment are relatively minor with appropriate mass production

technology.

The third long-term aim of GAVI is to encourage research on new and

improved vaccines for use in developing countries. The prospects for truly

important new vaccines have never been brighter3. Newer approaches

including mucosal immunization, nucleic acid vaccines, vectored vaccines

and even edible vaccines are making rapid progress. To move such

initiatives from preclinical research on laboratory animals to real-life

practice will be a monumental task. For vaccines as for pharmaceuticals,

the applied research and development, including clinical trials, are far

more expensive than the basic research. Furthermore, the skills for this

vital development work lie not within academia, but within industry. No

matter how well disposed industry leaders may be to furthering the

long-term ambitions of GAVI, in the end commercial realities dictate that

they do not embark on too many loss-making ventures. For diseases like

HIV/AIDS or even malaria, arguments can be mounted that there will be a

substantial market for a successful vaccine in industrialized countries.

But for diseases like bacillary dysentery this becomes much more difficult.

Thus there is room for a " fourth window " within GAVI, dealing with vaccine

research and development. How soon this window can be opened will depend

significantly on how the world as a whole reacts to the challenge laid down

by Bill Gates and President Bill Clinton. Simple arithmetic will show that

a fund capitalized at US$1=962 billion will not have the capacity to do all

that is asked of it. But in the context of a world where health is

approximately a US$3 trillion industry, one could envisage GAVI being much

bigger a decade from now.

Conclusions

One of the great glories of immunology is that it manages to span a huge

spectrum of endeavor. From the most fundamental probings into the molecular

genetics and cellular physiology of immune responses, to more applied

endeavors in vaccinology, autoimmunity, allergy, transplantation biology

and other branches of immunopathology, it extends not only into clinical

medicine, but epidemiology and public health. Within this great spectrum,

there are literally no discontinuities.

In the years 1950=961980 (as the foundations of new immunology were laid and

the field became a dominant force in biomedicine) the high priests and

priestesses of the discipline concerned themselves more with the academic

end of the spectrum and less with the community-oriented approaches which

actually had given birth to immunology. Things have changed now, and over

the last two decades it has been wonderful to see this imbalance being

redressed, with some of the best minds in immunology now heavily concerned

with the practical end. Thus the academic community has played its part in

creating a balanced structure.

But if spaceship Earth is really to derive maximum benefit, the most recent

immunization debate=97started in January 2000 at the World Economic

Forum=97must be widened and deepened to involve the whole global community.

As this story unfolds, GAVI should become the most effective public health

program in history.

=20

References 1. Fenner, F., , D. A., Arita, I., Jezek, Z. & Ladnyi,

I. D. Smallpox and its Eradication. (World Health Organization, Geneva,

1988). | PubMed |=20

2. Nossal, G. J. V. Global immunization: A partnership for the 21st

century. Science 284, 587 (1999). | Article | PubMed | ISI |=20

3. Nossal, G. J. V. in Fundamental Immunology 4th edn (ed. , W. E)

1387-1425 (Lippincott-Raven, Philadelphia,1999). | PubMed |=20

=20

=20

--------------------------------------------------------

Sheri Nakken, R.N., MA=09

Vaccination Information & Choice Network, Nevada City CA & UK

530-740-0561 Voicemail in US

http://www.nccn.net/~wwithin/vaccine.htm

" All that is necessary for the triumph of evil is that good men ( &

women) do nothing " ...Edmund Burke=20

ANY INFO OBTAINED HERE NOT TO BE CONSTRUED AS MEDICAL OR LEGAL ADVICE. THE=

=20

DECISION TO VACCINATE IS YOURS AND YOURS ALONE.

Well Within's Earth Mysteries & Sacred Site Tours

http://www.nccn.net/~wwithin=09

International Tours, Homestudy Courses, ANTHRAX & OTHER Vaccine Dangers

Education, Homeopathic Education

CEU's for nurses, Books & Multi-Pure Water Filters

----------

---

Outgoing mail is certified Virus Free.

Checked by AVG anti-virus system (http://www.grisoft.com).

Version: 6.0.273 / Virus Database: 143 - Release Date: 08/16/2001