A guide to vaccinology: from basic principles to new developments

Probably not a substantial claim: may not pass S3 (load-bearing).

The World Health Organization estimates that 2-3 million lives are saved each year by current immunization programmes.

“The World Health Organization (WHO) estimates that 2–3 million lives are saved each year by current immunization programmes”

• cites [2] World Health Organization. Child mortality and causes of death. WHO https://www.who.int/gho/child_health/mortality/mortality_under_five_text/en/ (2020).Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Although global coverage of 3 doses of the diphtheria-tetanus-pertussis vaccine has risen to more than 85%, more than 19 million children did not receive basic vaccinations in 2019.

“although global coverage of 3 doses of the diphtheria–tetanus–pertussis vaccine has risen to more than 85%, there are still more than 19 million children who did not receive basic vaccinations in 2019 (ref.105).”

• cites [105] World Health Organization. Immunization coverage. WHO https://www.who.int/news-room/fact-sheets/detail/immunization-coverage (2020).Not checked yet

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The portfolio of adjuvants is steadily expanding, with liposome-based adjuvants and oil-in-water emulsions being licensed in the past few decades.

“the portfolio of adjuvants is steadily expanding, with liposome-based adjuvants and oil-in-water emulsions being licensed in the past few decades14.”

• cites [14] Rappuoli, R., Mandl, C. W., Black, S. & De Gregorio, E. Vaccines for the twenty-first century society. Nat. Rev. Immunol. 11, 865–872 (2011). This paper presents a review of the role of vaccines in the twenty-first century, with an emphasis on increased life expectancy, emerging infections and poverty. sourceNot checked yet

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Individuals with deficiencies in the complement system are particularly susceptible to meningococcal disease caused by infection with Neisseria meningitidis because control of this infection depends on complement-mediated killing of bacteria.

“individuals with deficiencies in the complement system are particularly susceptible to meningococcal disease caused by infection with Neisseria meningitidis21 because control of this infection depends on complement-mediated killing of bacteria”

• cites [21] Fijen, C. A., Kuijper, E. J., te Bulte, M. T., Daha, M. R. & Dankert, J. Assessment of complement deficiency in patients with meningococcal disease in The Netherlands. Clin. Infect. Dis. 28, 98–105 (1999). sourceNot checked yet

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Some safe live attenuated vaccines require multiple doses and induce relatively short-lived immunity, for example the live attenuated typhoid vaccine Ty21a.

“some safe, live attenuated vaccines require multiple doses and induce relatively short-lived immunity (for example, the live attenuated typhoid vaccine, Ty21a)12”

• cites [12] Milligan, R., Paul, M., Richardson, M. & Neuberger, A. Vaccines for preventing typhoid fever. Cochrane Database Syst. Rev. 5, CD001261 (2018).Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Current immunization programmes contributed to the marked reduction in global mortality of children less than 5 years of age from 93 deaths per 1,000 live births in 1990 to 39 deaths per 1,000 live births in 2018.

“contributing to the marked reduction in mortality of children less than 5 years of age globally from 93 deaths per 1,000 live births in 1990 to 39 deaths per 1,000 live births in 2018 (ref.2).”

• cites [2] World Health Organization. Child mortality and causes of death. WHO https://www.who.int/gho/child_health/mortality/mortality_under_five_text/en/ (2020).Not checked yet

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Maternal vaccination with pertussis, tetanus and influenza vaccines reduces the risk of disease soon after birth and demonstrates the role of antibodies in protection against these diseases.

“Maternal vaccination with pertussis24, tetanus25 and influenza26 vaccines harnesses this important protective adaptation to reduce the risk of disease soon after birth and clearly demonstrates the role of antibodies in protection against these diseases.”

• cites [24] Sandmann, F. et al. Infant hospitalisations and fatalities averted by the maternal pertussis vaccination programme in England, 2012–2017: post-implementation economic evaluation. Clin. Infect. Dis. 71, 1984–1987 (2020). sourceNot checked yet

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• cites [25] Demicheli, V., Barale, A. & Rivetti, A. Vaccines for women for preventing neonatal tetanus. Cochrane Database Syst. Rev. 7, CD002959 (2015).Not checked yet

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• cites [26] Madhi, S. A. et al. Influenza vaccination of pregnant women and protection of their infants. N. Engl. J. Med. 371, 918–931 (2014). sourceNot checked yet

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Antibody-deficient individuals are susceptible to varicella zoster virus and other viral infections, but once infected they can control the disease in the same way as an immunocompetent individual so long as they have a normal T cell response.

“Antibody-deficient individuals are susceptible to varicella zoster virus (which causes chickenpox) and other viral infections, but, once infected, they can control the disease in the same way as an immunocompetent individual, so long as they have a normal T cell response23.”

• cites [23] Gershon, A. A. et al. Varicella zoster virus infection. Nat. Rev. Dis. Prim. 1, 15016 (2015). sourceNot checked yet

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The identification of correlates of protection is helpful in vaccine development because they can be used to compare products and to predict whether the use of an efficacious vaccine in a new population is likely to provide the same protection as that observed in the original setting.

“The identification of correlates of protection is helpful in vaccine development as they can be used to compare products and to predict whether the use of an efficacious vaccine in a new population (for example, a different age group, medical background or geographical location) is likely to provide the same protection as that observed in the original setting.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Human challenge studies have been used to determine correlates of protection, although the dose of challenge bacterium or virus and the experimental conditions may not relate closely to natural infection, which can limit the utility of these observations.

“Human challenge studies have also been used to determine correlates of protection, although the dose of challenge bacterium or virus and the experimental conditions may not relate closely to natural infection, which can limit the utility of these observations.”

May combine two claims.

Polysaccharide antigens can induce protective immune responses and are the basis of vaccines developed to prevent several bacterial infections, such as pneumonia and meningitis caused by Streptococcus pneumoniae, since the late 1980s.

“polysaccharide antigens can also induce protective immune responses and are the basis of vaccines that have been developed to prevent several bacterial infections, such as pneumonia and meningitis caused by Streptococcus pneumoniae, since the late 1980s9.”

• cites [9] Robbins, J. B. et al. Prevention of invasive bacterial diseases by immunization with polysaccharide–protein conjugates. Curr. Top. Microbiol. Immunol. 146, 169–180 (1989).Not checked yet

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Strategies to overcome original antigenic sin include the use of adjuvants that stimulate innate immune responses to induce sufficiently cross-reactive B cells and T cells, or the inclusion of as many strains in a vaccine as possible, the latter limited by the potential of new strains to emerge.

“Strategies to overcome this include the use of adjuvants that stimulate innate immune responses, which can induce sufficiently cross-reactive B cells and T cells that recognize different strains of the same pathogen, or the inclusion of as many strains in a vaccine as possible, the latter approach obviously being limited by the potential of new strains to emerge in the future54.”

• cites [54] Vatti, A. et al. Original antigenic sin: a comprehensive review. J. Autoimmun. 83, 12–21 (2017). sourceNot checked yet

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Original antigenic sin describes how the immune system fails to generate an immune response against a strain of a pathogen if the host was previously exposed to a closely related strain, and this has been demonstrated in dengue and influenza.

“This phenomenon describes how the immune system fails to generate an immune response against a strain of a pathogen if the host was previously exposed to a closely related strain, and this has been demonstrated in several infections, including dengue52 and influenza53.”

• cites [52] Halstead, S. B., Rojanasuphot, S. & Sangkawibha, N. Original antigenic sin in dengue. Am. J. Trop. Med. Hyg. 32, 154–156 (1983). sourceNot checked yet

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• cites [53] Kim, J. H., Skountzou, I., Compans, R. & Jacob, J. Original antigenic sin responses to influenza viruses. J. Immunol. 183, 3294–3301 (2009). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Another important feature of vaccine-induced protection is the induction of immune memory.

“Another important feature of vaccine-induced protection is the induction of immune memory.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Vaccines have been developed over the past two centuries to provide direct protection of the immunized individual through B cell-dependent and T cell-dependent mechanisms.

“Vaccines have been developed over the past two centuries to provide direct protection of the immunized individual through the B cell-dependent and T cell-dependent mechanisms described above.”

May combine two claims.

Acellular pertussis vaccine induces a shorter duration of protection against clinical pertussis and may be less effective against bacterial transmission than the whole-cell pertussis vaccine.

“It is now apparent that acellular pertussis vaccine induces a shorter duration of protection against clinical pertussis and may be less effective against bacterial transmission than is the whole-cell pertussis vaccine47.”

• cites [47] Chen, Z. & He, Q. Immune persistence after pertussis vaccination. Hum. Vaccin. Immunother. 13, 744–756 (2017). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Some vaccines may drive changes in responsiveness to future infections with different pathogens, so-called non-specific effects, perhaps by stimulating prolonged changes in the activation state of the innate immune system.

“Some vaccines may also drive changes in responsiveness to future infections with different pathogens, so called non-specific effects, perhaps by stimulating prolonged changes in the activation state of the innate immune system.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

T helper 1 cells and T helper 2 cells are mainly important for establishing cellular immunity and humoral immunity, respectively, although T helper 1 cells are also associated with generation of the IgG antibody subclasses IgG1 and IgG3.

“T helper 1 (TH1) cells and TH2 cells are mainly important for establishing cellular immunity and humoral immunity, respectively, although TH1 cells are also associated with generation of the IgG antibody subclasses IgG1 and IgG3.”

May combine two claims.

Breakthrough cases are less likely in individuals who have had two doses of measles-mumps-rubella vaccine or varicella zoster vaccine, and cases that do occur are usually mild, indicating some lasting immunity to the pathogen.

“Breakthrough cases are less likely in those individuals who have had two doses of measles–mumps–rubella vaccine50 or varicella zoster vaccine51, and cases that do occur are usually mild, which indicates that there is some lasting immunity to the pathogen.”

• cites [50] Paunio, M. et al. Twice vaccinated recipients are better protected against epidemic measles than are single dose recipients of measles containing vaccine. J. Epidemiol. Community Health 53, 173–178 (1999). sourceNot checked yet

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• cites [51] Zhu, S., Zeng, F., Xia, L., He, H. & Zhang, J. Incidence rate of breakthrough varicella observed in healthy children after 1 or 2 doses of varicella vaccine: results from a meta-analysis. Am. J. Infect. Control. 46, e1–e7 (2018). sourceNot checked yet

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May combine two claims.

Many high-income countries have observed a rise in pertussis cases since the introduction of the acellular vaccine, a phenomenon that is not observed in low-income nations using the whole-cell vaccine.

“Many high-income countries have observed a rise in pertussis cases since the introduction of the acellular vaccine, a phenomenon that is not observed in low-income nations using the whole-cell vaccine48.”

• cites [48] Burdin, N., Handy, L. K. & Plotkin, S. A. What is wrong with pertussis vaccine immunity? The problem of waning effectiveness of pertussis vaccines. Cold Spring Harb. Perspect. Biol. 9, a029454 (2017). sourceNot checked yet

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Modest vaccine coverage of 30-40% is likely to have an impact on seasonal influenza epidemics, but ≥80% coverage is likely to be optimal.

“Modest vaccine coverage, of 30–40%, is likely to have an impact on seasonal influenza epidemics, but ≥80% coverage is likely to be optimal56.”

• cites [56] Plans-Rubio, P. The vaccination coverage required to establish herd immunity against influenza viruses. Prev. Med. 55, 72–77 (2012). sourceNot checked yet

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If enough individuals in a population are vaccinated, and if vaccination prevents not only disease but also infection itself, transmission of the pathogen can be interrupted and the incidence of disease can fall further than would be expected because of indirect protection of susceptible individuals.

“if enough individuals in a population are vaccinated, and if vaccination prevents not only the development of disease but also infection itself (discussed in more detail below), transmission of the pathogen can be interrupted and the incidence of disease can fall further than would be expected, as a result of the indirect protection of individuals who would otherwise be susceptible.”

• AssumptionRests on an assumption: Vaccines cannot protect every individual in a population directly.

May combine two claims.

The waning of antibody levels varies depending on the age of the vaccine recipient, being very rapid in infants as a result of the lack of bone marrow niches for B cell survival, the nature of the antigen and the number of booster doses administered.

“The waning of antibody levels varies depending on the age of the vaccine recipient (being very rapid in infants as a result of the lack of bone marrow niches for B cell survival), the nature of the antigen and the number of booster doses administered.”

May combine two claims.

For infections that are manifest soon after acquisition of the pathogen, the memory response may be insufficient to control these infections and sustained immunity for individual protection through vaccination can be difficult to achieve.

“So, for infections that are manifest soon after acquisition of the pathogen, the memory response may be insufficient to control these infections and sustained immunity for individual protection through vaccination can be difficult to achieve.”

May combine two claims.

In high-income settings, many countries starting in the 1990s have switched to using the acellular pertussis vaccine, which is less reactogenic than the older whole-cell pertussis vaccine.

“in high-income settings, many countries (starting in the 1990s) have switched to using the acellular pertussis vaccine, which is less reactogenic than (and therefore was thought to be preferable to) the older whole-cell pertussis vaccine that is still used in most low-income countries.”

May combine two claims.

The evidence indicates that antibodies have the major role in prevention of infection, supported by T helper cells, whereas cytotoxic T cells are required to control and clear established infection.

“the evidence therefore indicates that antibodies have the major role in prevention of infection (supported by TH cells), whereas cytotoxic T cells are required to control and clear established infection.”

May combine two claims.

For influenza, the threshold for herd immunity is highly variable from season to season and is also confounded by the variability in vaccine effectiveness each year.

“For influenza, the threshold for herd immunity is highly variable from season to season and is also confounded by the variability in vaccine effectiveness each year55.”

• cites [55] Statista Research Department. Herd immunity threshold for selected global diseases as of 2013. Statista https://www.statista.com/statistics/348750/threshold-for-herd-immunity-for-select-diseases/ (2013).Not checked yet

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In the case of varicella zoster and measles-mumps vaccines, some breakthrough cases are described during disease outbreaks among individuals who have previously been vaccinated, although it is unclear whether this represents waned immunity or initial vaccine failure.

“In the case of varicella zoster and measles–mumps vaccines, some breakthrough cases are described during disease outbreaks among those individuals who have previously been vaccinated, although it is unclear whether this represents a group in whom immunity has waned (and who therefore needed booster vaccination) or a group for whom the initial vaccine did not induce a successful immune response.”

May combine two claims.

Evidence for the involvement of T cells in vaccine-induced protection is limited, likely owing in part to difficulties in accessing T cells to study and to not fully understanding which types of T cell should be measured.

“Although evidence for the involvement of T cells in vaccine-induced protection is limited, this is likely owing, in part, to difficulties in accessing T cells to study as only the blood is easily accessible, whereas many T cells are resident in tissues such as lymph nodes. Furthermore, we do not yet fully understand which types of T cell should be measured.”

May combine two claims.

T cell deficiency results in uncontrolled and fatal varicella zoster virus infection, whereas individuals with antibody deficiency readily develop infection but recover in the same way as immunocompetent individuals.

“T cell deficiency results in uncontrolled and fatal varicella zoster virus infection, whereas individuals with antibody deficiency readily develop infection but recover in the same way as immunocompetent individuals.”

May combine two claims.

Some vaccines, in addition to preventing disease, may also protect against asymptomatic infection or colonization, thereby reducing the acquisition of a pathogen and its onward transmission, establishing herd immunity.

“some vaccines, in addition to preventing the disease, may also protect against asymptomatic infection or colonization, thereby reducing the acquisition of a pathogen and thus its onward transmission, establishing herd immunity.”

May combine two claims.

Original antigenic sin might have important implications for vaccine development if only a single pathogen strain or pathogen antigen is included in a vaccine, as vaccine recipients might then have impaired immune responses if later exposed to different strains of the same pathogen, potentially putting them at increased risk of infection or more severe disease.

“This might have important implications for vaccine development if only a single pathogen strain or pathogen antigen is included in a vaccine, as vaccine recipients might then have impaired immune responses if later exposed to different strains of the same pathogen, potentially putting them at increased risk of infection or more severe disease.”

May combine two claims.

Although most evidence points to antibodies being the key mediators of sterilizing immunity induced by vaccination, most vaccines also induce T cell responses.

“Although most of the evidence points to antibodies being the key mediators of sterilizing immunity induced by vaccination, most vaccines also induce T cell responses.”

May combine two claims.

Vaccination of pregnant women against group B streptococci and respiratory syncytial virus has not yet been shown to be effective at preventing neonatal or infant infection, but it has the potential to reduce the burden of disease in the youngest infants.

“Vaccination of pregnant women against group B streptococci27 and respiratory syncytial virus (RSV)28 has not yet been shown to be effective at preventing neonatal or infant infection, but it has the potential to reduce the burden of disease in the youngest infants.”

• cites [27] Madhi, S. A. & Dangor, Z. Prospects for preventing infant invasive GBS disease through maternal vaccination. Vaccine 35, 4457–4460 (2017). sourceNot checked yet

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• cites [28] Madhi, S. A. et al. Respiratory syncytial virus vaccination during pregnancy and effects in infants. N. Engl. J. Med. 383, 426–439 (2020). sourceNot checked yet

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May combine two claims.

Polysaccharide vaccines do not induce T cell responses, as polysaccharides are T cell-independent antigens, and thus they must mediate their protection through antibody-dependent mechanisms.

“It is now known that these vaccines do not induce T cell responses, as polysaccharides are T cell-independent antigens, and thus they must mediate their protection through antibody-dependent mechanisms.”

May combine two claims.

From studies of individuals with inherited or acquired immunodeficiency, antibody deficiency increases susceptibility to acquisition of infection, whereas T cell deficiency results in failure to control a pathogen after infection.

“From studies of individuals with inherited or acquired immunodeficiency, it is clear that whereas antibody deficiency increases susceptibility to acquisition of infection, T cell deficiency results in failure to control a pathogen after infection.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The induction of herd immunity is perhaps the most important characteristic of immunization programmes, with each dose of vaccine protecting many more individuals than the vaccine recipient.

“Indeed, the induction of herd immunity is perhaps the most important characteristic of immunization programmes, with each dose of vaccine protecting many more individuals than the vaccine recipient.”

May combine two claims.

T cells induced by protein-polysaccharide conjugate vaccines recognize the protein carrier and provide help to B cells that recognize the polysaccharide, but no T cells are induced that recognize the polysaccharide, and thus only antibody is involved in the protection induced by these vaccines.

“The T cells induced by the vaccine recognize the protein carrier (a T cell-dependent antigen) and these T cells provide help to the B cells that recognize the polysaccharide, but no T cells are induced that recognize the polysaccharide and, thus, only antibody is involved in the excellent protection induced by these vaccines35.”

• cites [35] Pollard, A. J., Perrett, K. P. & Beverley, P. C. Maintaining protection against invasive bacteria with protein-polysaccharide conjugate vaccines. Nat. Rev. Immunol. 9, 213–220 (2009). This paper presents a review of the mechanism of action of polysaccharide vaccines and their role in establishing long-term protection against invasive bacteria. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The virus-like particles used in the HPV vaccine induce antibody responses that can persist for decades, whereas relatively short-term antibody responses are induced by pertussis vaccines, and the inactivated measles vaccine induces shorter-lived antibody responses than the live attenuated measles vaccine.

“the virus-like particles used in the HPV vaccine induce antibody responses that can persist for decades, whereas relatively short-term antibody responses are induced by pertussis vaccines; and the inactivated measles vaccine induces shorter-lived antibody responses than the live attenuated measles vaccine.”

May combine two claims.

In this situation, measles vaccination reduces mortality from measles as well as the unconnected diseases that would have occurred during the shadow, resulting in a benefit that seems to be non-specific but actually relates directly to the prevention of measles disease and its consequences.

“In this situation, measles vaccination reduces mortality from measles as well as the unconnected diseases that would have occurred during the ‘shadow’, resulting in a benefit that seems to be non-specific but actually relates directly to the prevention of measles disease and its consequences.”

May combine two claims.

Non-specific effects have been best described in humans in relation to BCG and measles vaccines, with several studies showing marked reductions in all-cause mortality when these vaccines are administered to young children that are far beyond the expected impact from the reduction in deaths attributed to TB or measles.

“This phenomenon has been best described in humans in relation to BCG and measles vaccines, with several studies showing marked reductions in all-cause mortality when these vaccines are administered to young children that are far beyond the expected impact from the reduction in deaths attributed to TB or measles, respectively66.”

• cites [66] Higgins, J. P. et al. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ 355, i5170 (2016). sourceNot checked yet

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Interference from maternal antibody is increasingly well documented and might reduce antigen availability, reduce viral replication in the case of live viral vaccines such as measles, or regulate B cell responses.

“One factor, which is increasingly well documented, is interference from maternal antibody72 — acquired in utero through the placenta — which might reduce antigen availability, reduce viral replication (in the case of live viral vaccines such as measles73) or perhaps regulate B cell responses.”

• cites [72] Voysey, M. et al. The influence of maternally derived antibody and infant age at vaccination on infant vaccine responses: an individual participant meta-analysis. JAMA Pediatr. 171, 637–646 (2017). sourceNot checked yet

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• cites [73] Caceres, V. M., Strebel, P. M. & Sutter, R. W. Factors determining prevalence of maternal antibody to measles virus throughout infancy: a review. Clin. Infect. Dis. 31, 110–119 (2000). sourceNot checked yet

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May combine two claims.

The HPV vaccine was originally introduced to control HPV-induced cervical cancer, with vaccination programmes directed exclusively at girls.

“The HPV vaccine was originally introduced to control HPV-induced cervical cancer, with vaccination programmes directed exclusively at girls”

May combine two claims.

Immune responses are poor in the older population and most of the vaccines used in older adults offer limited protection or a limited duration of protection, particularly among those older than 75 years of age.

“Immune responses are also poor in the older population and most of the vaccines used in older adults offer limited protection or a limited duration of protection, particularly among those older than 75 years of age.”

May combine two claims.

Converting plain polysaccharide vaccines into T cell-dependent protein-polysaccharide conjugate vaccines, which are immunogenic from 2 months of age and induce immune memory, has transformed prevention of disease caused by encapsulated bacteria (pneumococci, Hib and meningococci) over the past three decades.

“converting plain polysaccharide vaccines into T cell-dependent protein–polysaccharide conjugate vaccines, which are immunogenic from 2 months of age and induce immune memory, has transformed prevention of disease caused by the encapsulated bacteria (pneumococci, Hib and meningococci) over the past three decades78.”

• cites [78] Claesson, B. A. et al. Protective levels of serum antibodies stimulated in infants by two injections of Haemophilus influenzae type b capsular polysaccharide–tetanus toxoid conjugate. J. Pediatr. 114, 97–100 (1989). sourceNot checked yet

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Plain polysaccharide vaccines do not induce memory B cells and, even in adults, provide protection for just 2-3 years, with protection resulting from antibody produced by plasma cells derived from marginal zone B cells.

“These plain polysaccharide vaccines do not induce memory B cells (Fig. 6) and, even in adults, provide protection for just 2–3 years, with protection resulting from antibody produced by plasma cells derived from marginal zone B cells77.”

• cites [77] Peset Llopis, M. J., Harms, G., Hardonk, M. J. & Timens, W. Human immune response to pneumococcal polysaccharides: complement-mediated localization preferentially on CD21-positive splenic marginal zone B cells and follicular dendritic cells. J. Allergy Clin. Immunol. 97, 1015–1024 (1996). sourceNot checked yet

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May combine two claims.

Bone marrow niches to support B cells are limited in infancy, which might explain the very short-lived immune responses documented in the first year of life.

“bone marrow niches to support B cells are limited in infancy, which might explain the very short-lived immune responses that are documented in the first year of life74.”

• cites [74] Belnoue, E. et al. APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells. Blood 111, 2755–2764 (2008). sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based). May combine two claims.

In high-income countries, many older adults receive influenza, pneumococcal and varicella zoster vaccines, although data showing substantial benefits of these vaccines in past few decades in the oldest adults (more than 75 years of age) are lacking.

“In high-income countries, many older adults receive influenza, pneumococcal and varicella zoster vaccines, although data showing substantial benefits of these vaccines in past few decades in the oldest adults (more than 75 years of age) are lacking.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

A vaccine that prevents severe disease and disease-driven hospitalization for SARS-CoV-2 could have a substantial public health impact.

“a vaccine that prevents severe disease and disease-driven hospitalization could have a substantial public health impact.”

May combine two claims.

Vaccine study protocols are usually designed to find pathogen-specific effects, so the possibility of important non-specific effects cannot be assessed.

“as these are usually designed to find pathogen-specific effects, the possibility of important non-specific effects cannot be assessed.”

May combine two claims.

Non-specific effects may be particularly important in high-mortality settings, but not all studies have identified the phenomenon.

“These non-specific effects may be particularly important in high-mortality settings, but not all studies have identified the phenomenon.”

May combine two claims.

Apart from tetanus vaccine, all other vaccines in the routine immunization schedule induce some degree of herd immunity, which substantially enhances population protection beyond that which could be achieved by vaccination of the individual only.

“Apart from tetanus vaccine, all other vaccines in the routine immunization schedule induce some degree of herd immunity (Fig. 5), which substantially enhances population protection beyond that which could be achieved by vaccination of the individual only.”

May combine two claims.

There might be a downside to very high rates of vaccination, as the absence of pathogen transmission in that case will prevent natural boosting of vaccinated individuals and could lead to waning immunity if booster doses of vaccine are not used.

“there might be a downside to very high rates of vaccination, as the absence of pathogen transmission in that case will prevent natural boosting of vaccinated individuals and could lead to waning immunity if booster doses of vaccine are not used.”

May combine two claims.

Vaccination of older children and adults would induce stronger immune responses, but would be of little value if those who would have benefited from vaccination have already succumbed to the disease.

“vaccination of older children and adults would induce stronger immune responses, but would be of little value if those who would have benefited from vaccination have already succumbed to the disease.”

May combine two claims.

For T cell-independent antigens, animal data indicate that antibody responses depend on development of the marginal zone of the spleen, which is required for maturation of marginal zone B cells, and this does not occur until around 18 months of age in human infants.

“animal data indicate that antibody responses depend on development of the marginal zone of the spleen, which is required for the maturation of marginal zone B cells, and this does not occur until around 18 months of age in human infants76.”

• cites [76] Timens, W., Boes, A., Rozeboom-Uiterwijk, T. & Poppema, S. Immaturity of the human splenic marginal zone in infancy. Possible contribution to the deficient infant immune response. J. Immunol. 143, 3200–3206 (1989). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

It remains unclear how current immunization schedules might be adapted to improve population protection through non-specific effects.

“it remains unclear how current immunization schedules might be adapted to improve population protection through non-specific effects.”

May combine two claims.

Encapsulated bacteria (pneumococci, Hib and meningococci) are the most important invasive bacterial pathogens of childhood, causing most cases of childhood meningitis and bacterial pneumonia, and the development of conjugate vaccine technology in the 1980s has transformed global child health.

“These are the most important invasive bacterial pathogens of childhood, causing most cases of childhood meningitis and bacterial pneumonia, and the development of the conjugate vaccine technology in the 1980s has transformed global child health9.”

• cites [9] Robbins, J. B. et al. Prevention of invasive bacterial diseases by immunization with polysaccharide–protein conjugates. Curr. Top. Microbiol. Immunol. 146, 169–180 (1989).Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Surveys show vaccines are rarely delivered on schedule in many countries, so the published schedule may not be how vaccines are actually delivered on the ground.

“surveys show vaccines are rarely delivered on schedule in many countries and, thus, the published schedule may not be how vaccines are actually delivered on the ground.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Common side effects, particularly those associated with the early innate immune response to vaccines, are carefully documented in clinical trials.

“Common side effects, particularly those associated with the early innate immune response to vaccines, are carefully documented in clinical trials.”

May combine two claims.

Serious side effects from vaccines are very rare, with anaphylaxis being the most common of these rare side effects for parenteral vaccines, occurring after fewer than one in a million doses.

“Serious side effects from vaccines are very rare, with anaphylaxis being the most common of these rare side effects for parenteral vaccines, occurring after fewer than one in a million doses97.”

• cites [97] Bohlke, K. et al. Risk of anaphylaxis after vaccination of children and adolescents. Pediatrics 112, 815–820 (2003). sourceNot checked yet

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May combine two claims.

The route of administration can limit access; oral vaccines and nasal vaccines can be delivered rapidly on a huge scale by less-skilled workers, whereas most vaccines are injected, which requires more training to administer and takes longer.

“The route of administration can also limit access; oral vaccines (such as rotavirus, polio or cholera vaccines) and nasal vaccines (such as live attenuated influenza vaccine) can be delivered rapidly on a huge scale by less-skilled workers, whereas most vaccines are injected, which requires more training to administer and takes longer.”

May combine two claims.

The yellow fever vaccine is contraindicated in individuals with T cell immunodeficiency and occasionally causes a severe viscerotropic or neurotropic disease in individuals with thymus disease or after thymectomy, in young infants and adults more than 60 years of age.

“A particular risk of note is from the yellow fever vaccine, which is contraindicated in individuals with T cell immunodeficiency and occasionally causes a severe viscerotropic or neurotropic disease in individuals with thymus disease or after thymectomy, in young infants and adults more than 60 years of age88.”

• cites [88] Seligman, S. J. Risk groups for yellow fever vaccine-associated viscerotropic disease (YEL-AVD). Vaccine 32, 5769–5775 (2014). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Infant immunization schedules around the world are highly variable, and few high-income or middle-income countries use the Expanded Programme on Immunization schedule.

“infant immunization schedules around the world are highly variable — few high-income or middle-income countries use the Expanded Programme on Immunization schedule”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

For most vaccines that are used in the first year of life, 3-4 doses are administered by 12 months of age.

“For most vaccines that are used in the first year of life, 3–4 doses are administered by 12 months of age.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Lists of outbreak pathogens have been published by various agencies including the WHO.

“Lists of outbreak pathogens have been published by various agencies including the WHO108”

• cites [108] World Health Organization. Disease outbreaks. WHO https://www.who.int/emergencies/diseases/en/ (2020).Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Licensure of a new vaccine normally requires safety studies involving from 3,000 to tens of thousands of individuals.

“Licensure of a new vaccine normally requires safety studies involving from 3,000 to tens of thousands of individuals.”

May combine two claims.

Global vaccine coverage has stalled; coverage for diphtheria-tetanus-pertussis-containing vaccines has only risen from 84% to 86% since 2010.

“global vaccine coverage having stalled; for example, coverage for diphtheria–tetanus–pertussis-containing vaccines has only risen from 84% to 86% since 2010 (ref.104).”

• cites [104] Peck, M. et al. Global routine vaccination coverage, 2018. MMWR Morb. Mortal. Wkly. Rep. 68, 937–942 (2019). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The WHO DTP schedule was selected to provide early protection before levels of maternal antibody had waned and because vaccine compliance is better when doses are given close together.

“This schedule was selected to provide early protection before levels of maternal antibody had waned (maternal antibody has a half-life of around 30–40 days85, so very little protection is afforded to infants from the mother beyond 8–12 weeks of age) and because it was known that vaccine compliance is better when doses are given close together.”

• cites [85] Voysey, M., Pollard, A. J., Sadarangani, M. & Fanshawe, T. R. Prevalence and decay of maternal pneumococcal and meningococcal antibodies: a meta-analysis of type-specific decay rates. Vaccine 35, 5850–5857 (2017). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

Much has been written about the dangerous role of social media and online search engines in the spread of misinformation about vaccines and the rise of the anti-vaccination movement, but scientists are also at fault for failing to effectively communicate the benefits of vaccination to a lay public.

“Much has been written about the dangerous role of social media and online search engines in the spread of misinformation about vaccines and the rise of the anti-vaccination movement, but scientists are also at fault for failing to effectively communicate the benefits of vaccination to a lay public.”

May combine two claims.

Thiomersal has been voluntarily withdrawn from most vaccines by manufacturers as a precautionary measure rather than because of any scientific evidence of lack of safety and is currently used mainly in the production of whole-cell pertussis vaccines.

“Thiomersal has been voluntarily withdrawn from most vaccines by manufacturers as a precautionary measure rather than because of any scientific evidence of lack of safety and is currently used mainly in the production of whole-cell pertussis vaccines.”

May combine two claims.

Thiomersal has been used widely in vaccines since the 1930s without any evidence of adverse events associated with it, and there is no scientific evidence of any link between thiomersal and autism despite spurious claims.

“Thiomersal (also known as thimerosal) is an ethyl mercury-containing preservative that has been used widely in vaccines since the 1930s without any evidence of adverse events associated with it, and there is also no scientific evidence of any link between thiomersal and autism despite spurious claims about this102.”

• cites [102] DeStefano, F., Bodenstab, H. M. & Offit, P. A. Principal controversies in vaccine safety in the United States. Clin. Infect. Dis. 69, 726–731 (2019). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

For the poorest countries in the world, Gavi, the Vaccine Alliance provides funding to assist with new vaccine introductions and has greatly accelerated the broadening of access to new vaccines that were previously only accessible to high-income countries.

“For the poorest countries in the world, Gavi, the Vaccine Alliance provides funding to assist with new vaccine introductions and has greatly accelerated the broadening of access to new vaccines that were previously only accessible to high-income countries.”

May combine two claims.

Very rare side effects of vaccines are not usually observed during clinical development, with very few documented, and they are only recognized through careful surveillance in vaccinated populations.

“Very rare side effects of vaccines are not usually observed during clinical development, with very few documented, and they are only recognized through careful surveillance in vaccinated populations.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Despite access being the main issue affecting global vaccine coverage, a considerable focus is currently on the challenges posed by the anti-vaccination movement, largely as a result of worrying trends of decreasing vaccine coverage in high-income settings, leading to outbreaks of life-threatening infectious diseases, such as measles.

“Despite access being the main issue affecting global vaccine coverage, a considerable focus is currently on the challenges posed by the anti-vaccination movement, largely as a result of worrying trends of decreasing vaccine coverage in high-income settings, leading to outbreaks of life-threatening infectious diseases, such as measles.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Several spurious associations have been made between vaccines and various unrelated health conditions that occur naturally in the population.

“there have been several spurious associations made between vaccines and various unrelated health conditions that occur naturally in the population.”

May combine two claims.

From 1 in 55,000 to 1 in 16,000 recipients of an AS03-adjuvanted 2009 pandemic H1N1 influenza vaccine, who had a particular genetic susceptibility (HLA DQB1*0602), developed narcolepsy, although the debate continues about whether the trigger was the vaccine, the adjuvant or some combination, perhaps with the circulating virus also having a role.

“From 1 in 55,000 to 1 in 16,000 recipients of an AS03-adjuvanted 2009 pandemic H1N1 influenza vaccine98,99, who had a particular genetic susceptibility (HLA DQB1*0602)100, developed narcolepsy, although the debate continues about whether the trigger was the vaccine, the adjuvant or some combination, perhaps with the circulating virus also having a role.”

• cites [98] Nohynek, H. et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS ONE 7, e33536 (2012). sourceNot checked yet

  Not checked in the free run.

• cites [99] Miller, E. et al. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ 346, f794 (2013). sourceNot checked yet

  Not checked in the free run.

• cites [100] Hallberg, P. et al. Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival. EBioMedicine 40, 595–604 (2019). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Access to vaccines is currently limited, to varying degrees in different regions, by the absence of a health infrastructure to deliver vaccines, the lack of convenient vaccine provision for families, the lack of financial resources to purchase available vaccines and the marginalization of communities in need.

“Access to vaccines is currently limited, to varying degrees in different regions, by the absence of a health infrastructure to deliver vaccines, the lack of convenient vaccine provision for families, the lack of financial resources to purchase available vaccines (at a national, local or individual level) and the marginalization of communities in need.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In 2018, there were 140,000 deaths from measles worldwide, and the number of cases in 2019 was the highest in any year since 2006.

“In 2018, there were 140,000 deaths from measles worldwide, and the number of cases in 2019 was the highest in any year since 2006 (ref.107).”

• cites [107] World Health Organization. More than 140,000 die from measles as cases surge worldwide. WHO https://www.who.int/news-room/detail/05-12-2019-more-than-140-000-die-from-measles-as-cases-surge-worldwide (2019).Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Typically, diseases lacking commercial incentive have a restricted geographical spread (such as Rift Valley fever, Ebola, Marburg disease or plague) or occur in sporadic outbreaks and only affect poor or displaced communities (such as Ebola and cholera).

“Typically, these are diseases that have a restricted geographical spread (such as Rift Valley fever, Ebola, Marburg disease or plague) or occur in sporadic outbreaks and only affect poor or displaced communities (such as Ebola and cholera).”

May combine two claims.

About 6 days after measles-mumps-rubella vaccination, about 10% of 12-month-old infants develop a mild viraemia, which can result in fever and rash, and occasionally febrile convulsions (1 in 3,000).

“About 6 days after measles–mumps–rubella vaccination, about 10% of 12-month-old infants develop a mild viraemia, which can result in fever and rash, and occasionally febrile convulsions (1 in 3,000)86.”

• cites [86] Farrington, P. et al. A new method for active surveillance of adverse events from diphtheria/tetanus/pertussis and measles/mumps/rubella vaccines. Lancet 345, 567–569 (1995). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Recent funding initiatives, including those from US and European governments, have increased investment in the development of orphan vaccines.

“recent funding initiatives, including those from US and European governments, have increased investment in the development of orphan vaccines.”

May combine two claims.

More caution is required for the use of live attenuated, replicating vaccines (such as yellow fever, varicella zoster, BCG and measles vaccines) in the context of individuals with T cell immunodeficiency as there is a theoretical risk of uncontrolled replication, and live vaccines are generally avoided in this situation.

“More caution is required for the use of live attenuated, replicating vaccines (such as yellow fever, varicella zoster, BCG and measles vaccines) in the context of individuals with T cell immunodeficiency as there is a theoretical risk of uncontrolled replication, and live vaccines are generally avoided in this situation87.”

• cites [87] Pinto, M. V., Bihari, S. & Snape, M. D. Immunisation of the immunocompromised child. J. Infect. 72 (Suppl), S13–S22 (2016). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Even in immunocompromised individuals, there is no risk from use of inactivated, purified or killed vaccines, although the induction of immunity may not be possible, depending on the nature of the immune system defect.

“Even in immunocompromised individuals, there is no risk from use of these vaccines, although the induction of immunity may not be possible, depending on the nature of the immune system defect.”

• AssumptionRests on an assumption: Most vaccines in current use are inactivated, purified or killed organisms or protein and/or polysaccharide components of a pathogen and cannot replicate in the vaccine recipient.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The risk of hospitalization, death or long-term morbidity from the diseases for which vaccines have been developed is so high that the risks of common local and systemic side effects and the rare more serious side effects are far outweighed by the massive reductions in disease achieved through vaccination.

“The risk of hospitalization, death or long-term morbidity from the diseases for which vaccines have been developed is so high that the risks of common local and systemic side effects (such as sore arm and fever) and the rare more serious side effects are far outweighed by the massive reductions in disease achieved through vaccination.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Most vaccines must be refrigerated at 2-8 °C, requiring the infrastructure and capacity for cold storage and a cold chain to the clinic where the vaccine is delivered, which is limited in many low-income countries.

“most vaccines must be refrigerated at 2–8 °C, requiring the infrastructure and capacity for cold storage and a cold chain to the clinic where the vaccine is delivered, which is limited in many low-income countries.”

• AssumptionRests on an assumption: Most vaccines must be refrigerated at 2–8 °C.

May combine two claims.

Common side effects are very well known and are published by the regulator at the time of licensure.

“Thus, common side effects are very well known and are published by the regulator at the time of licensure.”

May combine two claims.

In a telephone survey in the USA, 23% of parents agreed with the statement 'Children get more immunizations than are good for them', and 25% indicated that they were concerned that their child's immune system could be weakened by too many immunizations.

“In a telephone survey in the USA, 23% of parents agreed with the statement ‘Children get more immunizations than are good for them’, and 25% indicated that they were concerned that their child’s immune system could be weakened by too many immunizations89.”

• cites [89] Gellin, B. G., Maibach, E. W. & Marcuse, E. K. Do parents understand immunizations? A national telephone survey. Pediatrics 106, 1097–1102 (2000). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Rare side effects might not be identified in clinical trials, but vaccine development is tightly controlled and robust post-marketing surveillance systems are in place in many countries, which aim to pick these up if they do occur.

“Although rare side effects might not be identified in clinical trials, vaccine development is tightly controlled and robust post-marketing surveillance systems are in place in many countries, which aim to pick these up if they do occur.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

CMV is a ubiquitous herpesvirus that is responsible for a significant burden of disease in infants; 15-20% of congenitally infected children develop long-term sequelae, most importantly sensorineural hearing loss, and CMV thus causes more congenital disease than any other single infectious agent.

“CMV is a ubiquitous herpesvirus that is responsible for a significant burden of disease in infants; 15–20% of congenitally infected children develop long-term sequelae, most importantly sensorineural hearing loss, and CMV thus causes more congenital disease than any other single infectious agent.”

May combine two claims.

Several HIV vaccines have been tested in clinical trials that were able to induce antibody responses (for example, RV144 vaccine showed 31% protection) and/or T cell responses, but these vaccines have not shown consistent evidence of protection in follow-up studies, and several studies found an increased risk of infection among vaccine recipients.

“several HIV vaccines have been tested in clinical trials that were able to induce antibody responses (for example, RV144 vaccine showed 31% protection109) and/or T cell responses, but these vaccines have not shown consistent evidence of protection in follow-up studies, and several studies found an increased risk of infection among vaccine recipients110.”

• cites [109] Rerks-Ngarm, S. et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N. Engl. J. Med. 361, 2209–2220 (2009). sourceNot checked yet

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• cites [110] Fauci, A. S., Marovich, M. A., Dieffenbach, C. W., Hunter, E. & Buchbinder, S. P. Immunology. Immune activation with HIV vaccines. Science 344, 49–51 (2014). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

There are several important diseases for which new vaccines are needed to reduce morbidity and mortality globally, which are likely to have a market in both high-income and low-income countries, including vaccines for group B Streptococcus, RSV and CMV.

“There are several important diseases for which new vaccines are needed to reduce morbidity and mortality globally, which are likely to have a market in both high-income and low-income countries, including vaccines for group B Streptococcus (a major cause of neonatal meningitis), RSV and CMV.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Seasonal influenza vaccines have, in recent decades, been used to protect vulnerable individuals in high-income countries, including older adults, children and individuals with co-morbidities that increase risk of severe influenza.

“Seasonal influenza vaccines have, in recent decades, been used to protect vulnerable individuals in high-income countries, including older adults, children and individuals with co-morbidities that increase risk of severe influenza.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Although BCG is the most widely used vaccine globally, with 89% of the world population receiving it in 2018, there is still a huge global burden of TB and it is clear that more effective TB vaccines are needed.

“Although BCG is the most widely used vaccine globally, with 89% of the world population receiving it in 2018 (ref.105), there is still a huge global burden of TB and it is clear that more effective TB vaccines are needed.”

• cites [105] World Health Organization. Immunization coverage. WHO https://www.who.int/news-room/fact-sheets/detail/immunization-coverage (2020).Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Vaccine-induced protection might be improved by the development of mammalian or insect cell-culture systems for growing influenza virus to avoid egg adaptation, and the use of MF59-adjuvanted vaccines and high-dose influenza vaccines to improve immune responses.

“Vaccine-induced protection might be improved by the development of mammalian or insect cell-culture systems for growing influenza virus to avoid egg adaptation, and the use of MF59-adjuvanted vaccines and high-dose influenza vaccines to improve immune responses.”

May combine two claims.

New malaria vaccines in development target more conserved antigens on the parasite surface or target different stages of the parasite life cycle.

“New malaria vaccines in development target more conserved antigens on the parasite surface or target different stages of the parasite life cycle.”

May combine two claims.

The licensed malaria vaccine, RTSS, provides only 30-40% protection and further work is needed to develop suitable products.

“the licensed malaria vaccine, RTSS, provides only 30–40% protection and further work is needed to develop suitable products111.”

• cites [111] Agnandji, S. T. et al. A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N. Engl. J. Med. 367, 2284–2295 (2012). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The application of RNA vaccines has been limited by their lack of stability and requirement for a cold chain.

“the application of RNA vaccines has been limited by their lack of stability and requirement for a cold chain”

• cites [130] Zhang, C., Maruggi, G., Shan, H. & Li, J. Advances in mRNA vaccines for infectious diseases. Front. Immunol. 10, 594 (2019). sourceNot checked yet

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• cites [131] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Questions remain about the duration of the effect of M72/AS01E, but the demonstrated efficacy can now be interrogated thoroughly to determine the nature of protective immunity against TB.

“Questions remain about the duration of the effect, but the demonstrated efficacy can now be interrogated thoroughly to determine the nature of protective immunity against TB.”

May combine two claims.

In HIV, antibodies can be generated that neutralize the virus, but the rapid mutation of the viral genome means that the virus can evade these responses within the same host.

“In the case of HIV, antibodies can be generated that neutralize the virus, but the rapid mutation of the viral genome means that the virus can evade these responses within the same host.”

May combine two claims.

For Neisseria gonorrhoeae and Treponema pallidum, antigenic targets for protective immune responses have not yet been determined, partly owing to limited investment and a poor understanding of the mechanisms of immunity at mucosal surfaces, or have thus far only resulted in limited protection.

“For other pathogens, such as Neisseria gonorrhoeae (which causes gonorrhoea) and Treponema pallidum (which causes syphilis), antigenic targets for protective immune responses have not yet been determined, partly owing to limited investment and a poor understanding of the mechanisms of immunity at mucosal surfaces, or have thus far only resulted in limited protection.”

Probably not a substantial claim: may not pass S3 (load-bearing).

A vaccine that effectively prevents congenital CMV infection would provide significant individual and public health benefits.

“A vaccine that effectively prevents congenital infection would provide significant individual and public health benefits.”

May combine two claims.

A lack of understanding of the nature of protective immunity against CMV has hampered vaccine development in the past, but the pipeline is now more promising.

“A lack of understanding of the nature of protective immunity against CMV has hampered vaccine development in the past, but the pipeline is now more promising119,120.”

• cites [119] Inoue, N., Abe, M., Kobayashi, R. & Yamada, S. Vaccine development for cytomegalovirus. Adv. Exp. Med. Biol. 1045, 271–296 (2018). sourceNot checked yet

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• cites [120] Schleiss, M. R., Permar, S. R. & Plotkin, S. A. Progress toward development of a vaccine against congenital cytomegalovirus infection. Clin. Vaccine Immunol. 24, e00268–e00317 (2017).Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

There is a growing subset of the population who are sceptical about vaccination.

“There is a growing subset of the population who are sceptical about vaccination”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

RSV causes a lower respiratory tract infection, bronchiolitis, in infancy and is the commonest cause of infant hospitalization in developed countries and globally one of the leading causes of death in those less than 12 months of age.

“RSV causes a lower respiratory tract infection, bronchiolitis, in infancy and is the commonest cause of infant hospitalization in developed countries and globally one of the leading causes of death in those less than 12 months of age.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Immunization protects populations from diseases that previously claimed the lives of millions of individuals each year, mostly children.

“Immunization protects populations from diseases that previously claimed the lives of millions of individuals each year, mostly children.”

Probably not a substantial claim: may not pass S4 (based).

Sociopolitical barriers stand in the way of safe and effective vaccination for all.

“Apart from the scientific challenges, sociopolitical barriers stand in the way of safe and effective vaccination for all.”

May combine two claims.

For some pathogens, there is likely to be a commercial market but there are immunological challenges for the development of new vaccines.

“For other pathogens, there is likely to be a commercial market but there are immunological challenges for the development of new vaccines.”

May combine two claims.

Nucleic acid-based vaccines need to be delivered directly into cells, requiring specific injection devices, electroporation or a carrier molecule, and this brings a risk of low transfection rate and limited immunogenicity.

“One of the disadvantages of these vaccines is that they need to be delivered directly into cells, which requires specific injection devices, electroporation or a carrier molecule and brings with it a risk of low transfection rate and limited immunogenicity129.”

• cites [129] Wallis, J., Shenton, D. P. & Carlisle, R. C. Novel approaches for the design, delivery and administration of vaccine technologies. Clin. Exp. Immunol. 196, 189–204 (2019). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Innovative delivery methods such as microneedle patches have potential advantages of improved thermostability, ease of delivery with minimal pain, and safer administration and disposal.

“innovative delivery methods, such as microneedle patches, are being developed, with the potential advantages of improved thermostability, ease of delivery with minimal pain and safer administration and disposal135”

• cites [135] Peyraud, N. et al. Potential use of microarray patches for vaccine delivery in low- and middle-income countries. Vaccine 37, 4427–4434 (2019). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

A viral vector expressing a TB protein, 85A, has been tested in a large TB-prevention trial in South Africa but this vaccine did not show protection, which was attributed by the authors to poor immunogenicity in the vaccinated children.

“A viral vector expressing a TB protein, 85A, has been tested in a large TB-prevention trial in South Africa but this vaccine did not show protection, which was attributed by the authors to poor immunogenicity in the vaccinated children116.”

• cites [116] Tameris, M. D. et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 381, 1021–1028 (2013). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Next-generation viral vectored or nucleic acid-based vaccines can be constructed using the pathogen genetic sequence only, thereby significantly increasing the speed of development and manufacturing processes.

“next-generation viral vectored or nucleic acid-based vaccines can be constructed using the pathogen genetic sequence only, thereby significantly increasing the speed of development and manufacturing processes125”

• cites [125] van Riel, D. & de Wit, E. Next-generation vaccine platforms for COVID-19. Nat. Mater. 19, 810–812 (2020). sourceNot checked yet

  Not checked in the free run.

• AssumptionRests on an assumption: Classic whole-organism vaccine platforms require the cultivation of the pathogen.

May combine two claims.

Insight into the atomic-level structure of the RSV F protein allowed stable expression of the pre-F protein, leading to strongly enhanced immune responses and providing proof of concept for structure-based vaccine design.

“insight into the atomic-level structure of the protein has allowed for stable expression of the pre-F protein, leading to strongly enhanced immune responses and providing a proof of concept for structure-based vaccine design132,133”

• cites [132] Crank, M. C. et al. A proof of concept for structure-based vaccine design targeting RSV in humans. Science 365, 505–509 (2019). This paper presents a phase I trial demonstrating enhanced immunogenicity of the pre-F conformation of RSV surface protein, thereby providing a proof of concept for successful structure-based vaccine design. sourceNot checked yet

  Not checked in the free run.

• cites [133] Mascola, J. R. & Fauci, A. S. Novel vaccine technologies for the 21st century. Nat. Rev. Immunol. 20, 87–88 (2020). sourceNot checked yet

  Not checked in the free run.

• AssumptionRests on an assumption: The RSV surface fusion (F) protein can exist in either a pre-fusion conformation, which facilitates viral entry, or a post-fusion form.
• AssumptionRests on an assumption: Previous RSV vaccines mainly contained the post-fusion form of the F protein.

May combine two claims.

Some individuals produce broadly neutralizing antibodies naturally, which target more conserved regions of the virus, leading to viral control, but it is not clear how to robustly induce these antibodies with a vaccine.

“Some individuals do produce broadly neutralizing antibodies naturally, which target more conserved regions of the virus, leading to viral control, but it is not clear how to robustly induce these antibodies with a vaccine.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The COVID-19 pandemic has shown that many parties with different incentives can come together to ensure that vaccines are being developed at unprecedented speed, but has also highlighted challenges of national and commercial interests.

“The COVID-19 pandemic has indeed shown that, in the case of an emergency, many parties with different incentives can come together to ensure that vaccines are being developed at unprecedented speed but has also highlighted some of the challenges of national and commercial interests.”

Probably not a substantial claim: may not pass S3 (load-bearing).

A licensed RSV vaccine would have a huge impact on infant health and paediatric hospital admissions.

“A licensed RSV vaccine would have a huge impact on infant health and paediatric hospital admissions.”

May combine two claims.

The optimal characteristics of a prophylactic TB vaccine, which antigens should be included and the nature of protective immunity remain unknown, despite more than 100 years of TB vaccine research.

“the optimal characteristics of a prophylactic TB vaccine, which antigens should be included and the nature of protective immunity remain unknown, despite more than 100 years of TB vaccine research.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

As many as 60 new RSV vaccine candidates are in development as either maternal vaccines or infant vaccines, or involving immunization with RSV-specific monoclonal antibodies that have an extended half-life.

“As many as 60 new RSV vaccine candidates are in development as either maternal vaccines or infant vaccines, or involving immunization with RSV-specific monoclonal antibodies that have an extended half-life.”

Probably not a substantial claim: may not pass S4 (based).

Variation in host response is an important factor to take into account.

“Moreover, it is becoming clear that variation in host response is an important factor to take into account.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The Coalition for Epidemic Preparedness Innovations (CEPI) is set to have a major role in funding and driving the development of vaccines against outbreak pathogens.

“The Coalition for Epidemic Preparedness Innovations (CEPI) is set to have a major role in funding and driving the development of vaccines against these pathogens.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

Access to vaccines is one of the greatest obstacles to safe and effective vaccination for all.

“Access to vaccines is one of the greatest obstacles”

Probably not a substantial claim: may not pass S4 (based).

Huge efforts have resulted in the licensure of a partially effective vaccine against malaria.

“Huge efforts have resulted in the licensure of a partially effective vaccine against malaria”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

An incomplete understanding of immune mechanisms of protection and the lack of solutions to overcome antigenic variability have hampered the design of effective vaccines against major diseases such as HIV/AIDS and TB.

“An incomplete understanding of immune mechanisms of protection and the lack of solutions to overcome antigenic variability have hampered the design of effective vaccines against major diseases such as HIV/AIDS and TB.”

May combine two claims.

Seasonal influenza vaccines take around 6 months to manufacture and have highly variable efficacy from one season to another, partly owing to the difficulty in predicting which virus strain will be circulating in the next influenza season, so that the vaccine strain may not match the strain causing disease.

“The vaccines take around 6 months to manufacture and have highly variable efficacy from one season to another, partly owing to the difficulty in predicting which virus strain will be circulating in the next influenza season, so that the vaccine strain may not match the strain causing disease113.”

• cites [113] Osterholm, M. T., Kelley, N. S., Sommer, A. & Belongia, E. A. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect. Dis. 12, 36–44 (2012). sourceNot checked yet

  Not checked in the free run.