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Vaccines: new thinking in immunisation

The advent of vaccines transformed diseases that were previously feared into almost medical curiosities. Mark Greener looks at examples of immunisation against common community diseases and how this cornerstone of public health continues to evolve

Mark Greener
BSc(Hons)
Freelance Medical Writer, Journalist
and Editor
Former Research Pharmacologist

Over the years, vaccines have saved countless lives and prevented untold suffering from once-common ailments, such as smallpox, polio and measles. (I suffered rubella and mumps as a child and can still recall just how unpleasant these were.) Vaccines remain a key line of defence against the seemingly inevitable influenza pandemic.

Moreover, vaccination is currently undergoing a renaissance. New vaccines tackle conditions as diverse as chickenpox, cervical cancer and even hypertension. Increasingly sophisticated immunological understanding informs schedules that maximise the protection afforded by vaccines against, for example, influenza and genital human papilloma virus.

A brief history of vaccination
In 429 BC, the Greek historian, Thucydides, noted that people who survived smallpox did not suffer the disfiguring, deadly disease a second time.1 The Chinese translated such observations into a practical therapy. Traditional Chinese healers inserted powdered scabs from pustules into the noses of children who had not yet contracted smallpox. The child was then immune for life.2

Vaccination in Europe began with Lady Mary Wortley Montagu, the wife of the British ambassador to Turkey. While in Constantinople, Lady Mary saw Turkish healers place a small quantity of a scab or tissue from a smallpox sore in a scratch on the surface of a child's skin. The child remained isolated during the resulting mild attack of smallpox. Lady Montagu publicised the technique (called variolation) when she returned to England in 1721 and public acceptability rose when the Princess of Wales had two of her children variolated.3 Unfortunately, 1–2% of those who underwent variolation died. Nevertheless, this still represented a marked improvement over the 30% mortality rate when people contracted smallpox naturally.4 In 1967, the World Health Organization (WHO) launched a programme to eradicate smallpox. The last natural case occurred in Somalia in 1977.5

Smallpox is not an isolated example of vaccination's importance. In the USA, vaccines reduced deaths from diphtheria, mumps, pertussis and tetanus by at least 99%.6 A recent WHO campaign cut polio incidence worldwide by 99.9%, raising the prospect that this debilitating, deadly disease will follow smallpox into the pages of medical history within a few years.7

The success of vaccination means that it is easy to forget just how disabling polio is. One in 200 polio infections produce permanent paralysis. Between 5–10% of those paralysed by polio die when the infection immobilises the respiratory muscles.8 The vaccination programmes against polio and smallpox represent major public health triumphs. As the WHO's Initiative for Vaccine Research states: "With the exception of water sanitation, no other modality – not even antibiotics – has had such a major effect on mortality reduction and population growth".7

Bolstering influenza defences
Vaccination will form a major line of defence against the predicted influenza pandemic, which is expected to threaten the lives of millions of people worldwide. The 1918 Spanish flu pandemic killed 40–100m people. Even epidemics can markedly increase mortality. According to the British Lung Foundation, the influenza epidemic of 1989–90 claimed around 20,000 and 30,000 extra lives in the UK.9

Clinicians first used inactivated influenza vaccines some 60 years ago and they remain the main line of defence against seasonal, epidemic and pandemic flu.10 The Department of Health (DH) estimates that 73.5% of people aged 65 years or over received the flu jab by the end of the 2007–08 season.

Just 45.3% of at-risk patients (such as those with cardiovascular disease, asthma or diabetes) aged six months to 65 years had received their shot.11 Put another way, more than a quarter of older people and over half of the high-risk group do not receive this potentially life-saving immunisation. In older people, inactivated influenza vaccines reduce hospitalisations for pneumonia and influenza by 27–33%; hospitalisations for respiratory conditions by 22–30%; and all-cause mortality by 47–50%. In high-risk patients aged 18–64 years, inactivated influenza vaccines reduce GP visits for acute respiratory disease or cardiovascular disease by 26%; hospitalisations for these conditions by 87%; and all-cause mortality by 78%.12 Nurses need to take every opportunity to remind eligible patients to attend for their jab.

Nevertheless, influenza vaccine is less effective among adults aged 60 years or over compared to younger adults. However, a new intradermal injection system may boost the vaccine's efficacy in older people. In a randomised study, 3,701 subjects aged 60–94 years received the same trivalent vaccine by intramuscular or intradermal injection. Seroprotection rates were between 5.5% and 6.6% higher in the intradermal group, depending on the influenza strain. Mean titre (antibody level) increases after intradermal vaccination were 24.5%, 53.1% and 18.8% higher for the influenza strains H1N1, H3N2 and B, respectively, compared with intramuscular administration. The increased antibody responses should enhance the vaccine's ability to protect against influenza in the elderly.13

Meanwhile, a recent study makes a strong case for universal vaccination. In 2000, the Canadian province of Ontario started vaccinating the entire population aged six months or older. Over the next four years, influenza-associated mortality for the overall population decreased by 74%. This compared with a fall of 57% in other Canadian provinces, which retained targeted immunisation. Furthermore, influenza-associated hospitalisations declined by an additional 42% in Ontario compared with the other provinces. Visits to emergency departments and doctors because of influenza fell by 55% and 59% respectively more in Ontario.

In theory, influenza-associated deaths and healthcare use may have decreased more in Ontario because of other unidentified factors. Nevertheless, universal vaccination seems to reduce mortality and healthcare use, particularly in people under the age of 65. Importantly, despite extensive publicity, only an estimated average of 38% of households participated. This means that the benefits of truly universal vaccination could be even more marked than these figures suggest.14

A constant struggle
Despite their success, vaccine developers are engaged in a constant struggle against influenza's ability to mutate. Influenza A contains eight genes that encode 10 proteins, including haemagglutinin (HA), neuraminidase (NA) and three polymerases (enzymes that manufacture the viral genetic code). Microbiologists characterise influenza A – the type of the virus that causes human pandemics - by typing haemagglutinin (HA) and neuraminidase (NA). Numerous variants exist in influenza in nature; 16 and nine of HA and NA respectively in the flu strains that infect aquatic birds, for example. However, only three and two respectively cause human epidemics.
Pandemics usually occur when influenza evolves a novel HA - and less commonly NA – that the immune system does not recognise and that can spread efficiently through the population.15

Most of these immunologically novel strains arise when regions of the influenza genome move between flu strains (called reassortment). In 1957, for example, avian H2N2 and human H1N1 simultaneously infected a single animal, probably a human. Reassortment produced a new influenza virus – H2N2 (Asian influenza) – containing the genes for HA, NA and one polymerase protein from the avian virus. The remaining genes derived from the human virus. Asian influenza killed four million people. However, a purely avian H1N1 probably caused the 1918 pandemic. Mutations in a polymerase conferred the ability to spread readily between humans.15,16

As a result, government and nongovernmental organisations monitor isolates to identify the strains that emerge from reassortment cauldrons, such as parts of the world where humans and animals live in close proximity. Such monitoring informs the development of the seasonal vaccines, and should offer an early warning of an epidemic or pandemic strain. H5N1 – bird flu – is the usual suspect for leaping across the species barrier and triggering a pandemic. Nevertheless, the pig virus H9N2 "may be at least equally plausible" as a candidate for the cause of the next pandemic.16

Vaccination is the keystone of attempts to control the flu pandemic, whatever the origin. Certainly, antivirals are important, especially while manufacturers scale up vaccine production. Indeed, the 1918 pandemic strain was susceptible to amantadine and NA inhibitors, such as oseltamivir.17 If supplies are limited, combination therapy may allow more patients to receive antivirals during a pandemic. The kidney excretes oseltamivir through glomerular filtration and tubular secretion. Probenecid blocks tubular secretion. So combining oseltamivir with probenecid increases the steady state blood concentrations of the antiviral 2.5-fold and allows alternate day dosing.17

However, recent reports raise the prospect of increasing resistance to oseltamivir, further emphasising vaccination's importance during a pandemic. The H1N1 strain accounted for around a fifth of circulating flu viruses in the US collected during the 2007/8 season. Twelve percent of the isolates were resistant to oseltamivir. Preliminary data from the 2008/9 season suggest a marked increase in the number of resistant strains.18

Vaccines "were not available in significant quantities" during the 1957 and 1968 pandemics, which probably contributed to the high death toll.19 Reassuringly, modern vaccines are highly effective. One recent study recruited volunteers who received an experimental H5N3 vaccine between 1999 and 2001. More than 80% of volunteers showed protective titres against all strains of H5 (even those not covered by the vaccines) within a week of receiving a single low-dose booster of an updated H5N1 jab. This compared to 20% in those who had not received the H5N3 vaccine. These subjects needed two doses and achieved protective titres after six weeks.20

So, behind the headlines, there's been remarkably rapid progress to develop vaccines that could prevent – or at least tame – the next pandemic. And, of course, recent concerns over the outbreak of H1N1 that spread worldwide from Mexico underscore the difficulties of predicting the biological or geographical source of the next pandemic. By next year, vaccine producers should be potentially able to produce sufficient vaccine to immunise 4.5 billion people. Vaccines will probably save millions of lives when the next pandemic arrives.21

A vaccine against cancer
The high-profile death of Jade Goody has brought cervical cancer into the spotlight. More than 80% of sexually active women contract a genital human papilloma virus (HPV) infection at least once before their 50th birthday. Most HPV infections are transient and asymptomatic. However, persistent infection with certain HPV strains (notably 16 and 18) can lead to precancerous lesions and, ultimately, cervical cancer.22
According to Cancer Research UK, doctors diagnosed 2,803 cases of cervical cancer in the UK during 2005. In 2006, cervical cancer killed 949 women.23

HPV vaccination marked one of the most fundamental changes to immunisation schedules for decades. According to the DH, Cervarix – the vaccine used in the programme – "will guard against the two strains of the HPV virus, which cause 70% of cases of cervical cancer." The DH expects that vaccination will save around 400 lives a year.24 However, questions are beginning to emerge about the current target group and whether the DH chose the best vaccine.

For example, research presented at the International Congress on Anti-Cancer Treatment examined more than 17,000 women aged 16–26 years who had either never had sex, who had but were unexposed to HPV, or who had been exposed to types 6, 11, 16 or 18. Gardasil prevented 30 cases of precancerous cervical lesions per 10,000 women previously unexposed to HPV. This compares to 40 cases per 10,000 women previously exposed to HPV. If confirmed, such findings may increase the pressure on the government to expand coverage.

Cervarix protects against two HPV strains (16 and 18) responsible for cervical cancer. Gardasil covers four strains (6, 11, 16 and 18). HPV types 6 and 11 are associated with more than 90% of the benign lesions associated with HPV, such as genital warts and juvenile respiratory papillomatosis.25 Therefore, in addition to protecting against most cases of cervical cancer, Gardasil reduces the risk of anogenital warts. So should the DH have taken the opportunity to protect patients from noncancerous HPV lesions?

A survey of genitourinary medicine clinics in 2003 found that managing genital warts cost £22.4m annually.26 Primary care costs further increase the economic burden. Between 1998 and 2000, GPs diagnosed 20.9% and 16.5% of genital warts in women and men, respectively.27 However, £25m or £30m is a drop in the NHS's budgetary ocean. In 2008–09, the NHS budget will be £96bn. So while Gardasil may seem a more logical choice clinically, the DH has to ensure that they make the most effective use of our tax pounds – which is why they chose Cervarix. Whether they made the right choice remains a  moot point.

Vaccination against chickenpox
Cost is also one influential factor that will determine whether varicella-zoster virus (VZV) vaccines become a standard part of the childhood immunisation schedule. VZV is one of eight human herpes viruses that evolved into a distinct clade (a taxonomic group with a final common ancestor) some 400 million years ago.28 Since then, VZV evolved in parallel with humans, resulting in a highly contagious virus.

Varicella usually affects children aged between two and eight years.29 However, the epidemiology seems to be shifting. In the UK, between 1983 and 1998 the number of cases roughly halved in children aged five to 14 years old and fell by almost a third in those aged between 15 and 44 years. Meanwhile, the number of cases in those aged four years and under doubled. In part, these shifts may reflect increased contact between preschool children, such as in playgroups and day care.30

In most cases, especially among children, chickenpox just means spending a few days "under the weather". However, one in 20 people develop complications after they contract VZV, which can include bacterial infections of the blisters and sores (making scars much more likely), meningitis, encephalitis, pneumonia, bronchitis and otitis media.31 One in every 7,000 children with chickenpox needs hospital treatment. One in 10 of these children develops serious complications – such as severe scarring, nerve damage leading to movement problems, damage to the valves in the heart and epilepsy.32 

Vaccine prevents more than four fifths of all chickenpox cases and more than 19 in every 20 cases of severe disease.33 Currently, however, the Joint Committee on Vaccination and Immunisation (JCVI) recommends varicella immunisation only for nonimmune healthcare workers in primary care as well as NHS and private hospitals who have direct patient contact. Nurses and other healthcare workers who had not suffered from either chickenpox or shingles should receive a blood test to check their immunity.34 Whether the VZV vaccine becomes more widely available will depend on academics and manufacturers marshalling compelling clinical and
economic argument.

Vaccination is a routine part of many nurses' day-to-day practice. However, vaccination is one of the most important and one of the most effective of all nursing interventions. In the future nurses could vaccinate against an even wider range of diseases. Indeed, in some diseases – most notably cancer – vaccines can even treat a disease. In cancer, these therapeutic vaccines trigger the immune system to mount a reaction against the malignancy.

Furthermore, the Angiotensin Therapeutic Vaccine (ATV) is a conjugate vaccine containing a peptide analogue of angiotensin I cross-linked to a carrier protein and could allow vaccination in, for example, people with hypertension who do not comply with treatment. ATV stimulates the immune system to produce antibiotics that neutralise angiotensin I, one of the hormones that control blood pressure.35 Another vaccine for hypertension – CYT006-AngQb – induces antibodies specific for angiotensin II. Patients who received three shots of 300 μg CYT006-AngQb showed a reduction of mean ambulatory daytime blood pressure of 9.0/4.0 mmHg compared with placebo.36 

As these examples illustrate, new schedules, new technology and new vaccines will ensure that the immunisation success story will continue in an ever-broader range of diseases. As one review commented: vaccination "is perhaps the most powerful of all medical interventions".37

References
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