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Вакцинация в современном мире
E. David G. McIntosh1’ 2
1 Scientific Center for Children's Health of Russian Academy of Medical Science
2 Imperial College, London
Immunisation Update 2011
Correspondence:
E. David G. McIntosh, Honorary Professor, Scientific Center for Children's Health, Russian Academy of Medical Science e-mail: [email protected]
Accepted: 09.07.2011, submitted for publication: 11.07.2011.
Introduction
This article aims to highlight some of the «hot topics» in immunisation in 2011. There are four sections:
1) Adjuvants: these enhance immunogenicity and can, for example, provide heterologous coverage for influenza vaccines.
2) The immunocompromised host: focused especially on vaccines against influenza and cytomegalovirus (CMV).
3) Therapeutic vaccines: for example sipuleucel-T for advanced prostatic cancer, DNA vaccines for bacterial infections, and early and late protection against tuberculosis.
4) Outbreaks and travel: cholera vaccination — a change in strategy, and meningococcal vaccination.
Adjuvants
The possibility of an improved breadth of response, with the addition of MF59 adjuvant to influenza vaccine in infants and young children (6-59 months of age), has been demonstrated (O’Hagan et al. 2011; Vesikari et al. 2009). Studying two influenza vaccines, both containing the A/Wisconsin/67/2005 (H3N2)-like virus antigen which was recommended for the 2006-2007 influenza season, the ratio of the geometric mean titres (GMTs) in young children immunized with a subunit influenza vaccine adjuvanted with MF59 over the GMTs in similar individuals immunized with a non-adjuvanted split influenza vaccine, there is a level of enhancement achieved for the heterologous strain A/New York/55/2004 (H3N2) consistent with that shown for the homologous strain A/Wisconsin/67/2005 (H3N2). The same was observed for vaccine containing the A/Panama/2007/1999 (H3N2)-like virus antigen recommended for the 2003-2004 influenza season, with enhancement achieved for the heterologous strain, A/Wyoming/3/2003 (H3N2)-like, which was very closely related to the A/Fujian strain that actually circulated in this season.
It appears that inclusion of MF59 adjuvant in the influenza vaccine enabled better coverage against a heterologous circulating strain following a vaccine ‘mismatch’. This is not to say that we should only recommend adjuvanted influenza vaccines. The important thing is to vaccinate against influenza with the vaccine which is available and recommended. Now that influenza A (H1N1) pandemic strain is incorporated into the seasonal influenza vaccine and with the continued circulation of that virus, it is as important as ever for routine influenza immunisation to be offered.
The immunocompromised host
Staying with influenza, a summary of influenza frequency and case fatality in hematopoietic stem cell transplant and cancer patients has been published (Sommer et al. 2006;
Decker and Safdar, 2010). The findings covered influenza seasons from 1989 to 2002 and thousands of patients. The frequency of influenza during the total observation period ranged from 0% up to 33%, while the case fatality also ranged from 0% up to 33%. With diverse seasons and patient types, this reflects a potential preventable burden of disease in those at high risk. Furthermore, a number of studies show that such oncology patients achieve seroconversion rates nearly as high as rates in healthy controls, when they are vaccinated appropriately (Sommer et al. 2006; Decker and Safdar, 2010).
But influenza is only one of many viruses that have the potential to cause morbidity and mortality in oncology patients. Another virus is CMV. As yet, there is no licensed vaccine for the prevention of CMV. Great reliance is placed on immunoglobulin and antiviral agents such as ganciclovir for the purpose of prophylaxis and treatment of CMV infections. A number of candidate CMV vaccines have been studied in Phase I and Phase II clinical trials, not only in healthy subjects but also in oncology patients. The results so far are promising, with good immune responses and safety profiles (Sung and Schleiss, 2010).
Therapeutic vaccines
Sipuleucel-T (known by its brand name as Provenge) is effectively a vaccine, or perhaps more correctly an autologous cellular immunotherapy, which induces and immune response against prostatic acid phosphatase (PAP). PAP is generally expressed by most prostate cancers. Sipuleucel-T is indicated for the treatment of certain types of prostatic cancer. Whilst obviously not a paediatric condition, it is nevertheless instructive to understand how the body’s immune system is harnessed in this way to improve survival in such cancer patients. The primary efficacy of sipuleucel-T is a reduction in the hazard ratio from 1.0 to 0.78 (p = 0.03), with a hazard ratio for overall survival of 0.65 (p = 0.009) (Kantoff et al. 2010; Madan and Gulley, 2011). Of more direct interest to infectious diseases, DNA vaccines are being developed to target bacterial infections (Ingolliti et al. 2010). According to the authors of the review, DNA vaccines involve the injection of a DNA plasmid containing a transgene that encodes the sequence of a target protein from a pathogen under the control of a eukaryotic promoter. This induces both long-lasting humoral and cellular immune responses. Multiple methods exist to enhance the immuno-genicity of DNA vaccines at including codon optimization, molecular adjuvants and electroporation.
Four DNA vaccines for larger animals are licensed for veterinary use. DNA vaccines have advantages over existing vaccines platforms, making them a suitable option for controlling bacterial infectious disease in the era of antibiotic resistance. The development of peptides that
mimic carbohydrate antigens have opened the possibility to induce T-lymphocyte-dependent polysaccharide immunity by the injection of a DNA vaccine.
DNA vaccines targeting bacterial pathogens such as Helicobacter pylori, M. tuberculosis and Bacillus anthracis have been tested with encouraging results. Other DNA vaccines are currently under development against such diverse pathogens as Streptococcus pneumoniae, Group A and Group B streptococcus, Haemophilus influenzae type b, Clostridium tetani, Clostridium botulinum, Salmonella typhi, Neisseria meningitidis, Vibrio cholera, Listeria monocytogenes, Pseudomonas aeruginosa, E. coli, staphylococcus, chlamydia, mycoplasma, yersinia and anthrax.
Of particular interest in the field of therapeutic vaccines is a tuberculosis vaccine designed to protect not only against early disease but also to protect against the establishment of latent persistent infection and reactivation of clinical disease (Aagaard et al. 2011; Tse 2011). This is a vaccine comprising antigens that are expressed in both the early and the late stages of tuberculosis, and appears able to combat late-stage infection both pre- and post-exposure.
The vaccine (H56) is made up of a fusion protein (Ag85B-ESAT6-Rv2660c) plus an adjuvant and:
• ESAT6 which is a 6 kDa early secretory antigenic target.
• Ag85B and ESAT6 are well-known Mycobacterium tuberculosis antigens that are secreted early in infection.
• Rv2660c, involved in the «stress response» is a factor expressed throughout the various stages of the tuberculous infection — it is a latency-associated protein.
H56 has been shown to control reactivation and significantly lower the mycobacterial load in mice when compared with adjuvant control. There is now hope that a next-generation tuberculosis vaccine will become available, to replace the current BCG vaccines.
Outbreaks and travel
A proposal has been made for a new strategy to combat cholera outbreaks (Reyburn et al. 2011; Sinclair et al. 2011). The currently available oral killed whole cell vaccines can prevent 50 to 60% of cholera episodes during the first two years after the primary vaccination schedule. The impact and cost-effectiveness of adopting oral cholera vaccines into the routine vaccination schedule of endemic countries depends on the prevalence of cholera, the frequency of epidemics and access to basic services providing rapid rehydration therapy. In October 2009, the World Health Organization's (WHO) Strategic Advisory Group of Experts (SAGE) on immunization
made the pivotal recommendation that oral cholera vaccination should be considered as a reactive strategy in areas with ongoing outbreaks. This is in addition to the continuing recommendation that oral cholera vaccines be used in areas where the disease is endemic and should be considered in areas at risk for outbreaks in conjunction with other prevention and control strategies.
Previously, the WHO did not recommend oral cholera vaccination once an outbreak had started due to «the time required to reach protective efficacy and the high cost and heavy logistics associated with its use». This reluctance has since changed because of the emergence of large and prolonged outbreaks, particularly in sub-Saharan Africa. For example, the large cholera outbreak in Zimbabwe is the latest of these catastrophes. By 2008, 179,323 (94%) of the reported 190,130 global cholera cases and 5,074 (99%) of 5,143 global cholera deaths reported to the WHO occurred in Africa.
Finally, moving to new recommendations for the use of quadrivalent meningococcal conjugate vaccine (covering serogroups A, C, W135 and Y), authorities in the UK recommend that all travellers should undergo a careful risk assessment that takes into account their itinerary, duration of stay and planned activities (Department of Health). Individuals who are particularly at risk are visitors who live or travel «rough», such as backpackers and those living or working with local people. The recommendations for use of the quadrivalent meningococcal vaccine for travel are that:
• In infants and children < 5 years of age, quadrivalent conjugate vaccine is recommended because of the improved immune response and reduced risk of hyporesponsiveness.
• In those 5 years of age and older, the quadrivalent conjugate vaccine should be given to provide better and longer lasting protection.
In the not-too-distant-future it is hoped that a meningococcal vaccine covering serogroup B will become available.
Summary and conclusions
There are a number of new developments in vaccines including the addition of new adjuvants and research on therapeutic vaccines. Specific groups such as the immunocompromised may enjoy improved protection from new vaccines. And those at risk of meningococcal infection through travel or other exposure may soon have the option to be protected against the great majority of meningococcal serogroups.
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