Early vaccine advocacy: Medals honoring Edward Jenner issued during the 19th century

The results from the first vaccination experiments published by Edward Jenner in 1798 were widely disseminated and consequently Jennerian vaccination was rapidly introduced in Europe and elsewhere. One of the reasons for the rapid spread of vaccination was that Jenner championed the procedure as a public health tool and not just as a mean to achieve individual protection. Vaccination was promoted by the highest levels of government in Germany where the vaccine was introduced in 1799 and also in France, where the vaccine arrived in 1800. Medals were used to promote vaccination both rewarding parents of vaccinated children as well as meritorious vaccinators. The first medal mentioning the name of Jenner was minted in Germany in 1803 followed by others, minted in Germany, Italy, France and England. Numerous other vaccine medals were made during the 19th century as an early and little known approach to advocating for vaccination.     

Interpreting the epidemiology of postexposure vaccination against smallpox

Six historical studies were investigated to clarify the obtainable information on postexposure vaccination against smallpox. Using the distribution of incubation period, the frequency of cases by time from exposure to vaccination was obtained. More than half of all failures happened within 7 d after exposure in all six records investigated. Based on two studies (n=36 and 28), the probability of escaping severe smallpox was further analyzed using logistic regression, showing an inverse association between severe smallpox and time from vaccination to onset (p<0.01 and p=0.04, respectively). Whereas the relationship between the probability of developing severe disease and the time from vaccination to onset could be analyzed with the available information, our findings indicate that previous epidemiologic records showing cases alone, rather than also showing individuals probably protected, are not useful for clarifying the effectiveness of postexposure vaccination by time after exposure.     

Three different paths to introduce the smallpox vaccine in early 19th century United States

The ancient technique of variolation (inoculation of the smallpox) which was introduced in the United States in 1721 was replaced by vaccination (inoculation of the cowpox) soon after the procedure was published by Edward Jenner in 1798. Benjamin Waterhouse is recognized as the introducer of smallpox vaccination in the United States having conducted the first vaccination in Boston on 8 July 1800, although other American physicians also played an important role in extending vaccination in the East Coast of the United States. A different route of introduction brought the smallpox vaccine from Mexico to New Mexico (March 1805) and Texas (April 1806) which at that time where part of the Viceroyalty of New Spain. The vaccine was brought to California in 1817 by Russian merchants who obtained it in Peru, where the vaccine had arrived in 1806 with the Spanish Philanthropic Expedition of the Vaccine. It took almost 150 years of vaccination efforts before the last natural outbreak of smallpox occurred in the United States in 1949.     

A randomized,double-blind,dose-finding Phase II study to evaluate immunogenicity and safety of the third generation smallpox vaccine candidate IMVAMUNE

IMVAMUNE^® is a Modified Vaccinia Ankara (MVA)-based virus that is being developed as a safer 3rd generation smallpox vaccine. In order to determine the optimal dose for further development, a double-blind, randomized Phase II trial was performed testing three different doses of IMVAMUNE^® in 164 healthy volunteers. All three IMVAMUNE^® doses displayed a favourable safety profile, with local reactions as the most frequent observation. The 1 × 10⁸ TCID₅₀ IMVAMUNE^® dose induced a total antibody response in 94% of the subjects following the first vaccination and the highest peak seroconversion rates by ELISA (100%) and PRNT (71%). This IMVAMUNE^® dose was considered to be optimal for the further clinical development of this highly attenuated poxvirus as a safer smallpox vaccine.     

Phenotypic and genetic diversity of the traditional Lister smallpox vaccine

As an initial step in the development of a second-generation smallpox vaccine derived from the Lister strain, to be prepared for a variola virus threat, diversity of the traditional vaccine was examined by characterizing a series of ten viral clones.     

Sex difference in immune response to vaccination: A participant-level meta-analysis of randomized trials of IMVAMUNE® smallpox vaccine

IntroductionPrevious research shows immune response to vaccination differs by sex but this has not been explored for IMVAMUNE^®, a replication-deficient smallpox vaccine developed in response to the potential for bioterrorism using smallpox.MethodsWe conducted a participant-level meta-analysis (N = 275, 136 men, 139 women) of 3 randomized trials of IMVAMUNE conducted at 13 centers in the US through a federally-funded extramural research program. Studies were eligible for inclusion if they tested the standard dose (1 × 10⁸ TCID₅₀/mL on Days 0 and 28) of liquid formulation IMVAMUNE, were completed at the time of our search, and enrolled healthy vaccinia-naïve participants. Models of the peak log₂ ELISA and PRNT titers post-second vaccination were constructed for each study with sex as a covariate. Results from these models were combined into random effects meta-analyses of the sex difference in response to IMVAMUNE. We then compared this approach with fixed effects models using the combined participant level data.ResultsIn each study the mean peak log₂ ELISA titer was higher in men than women but no single study demonstrated a statistically significant difference. Combination of the adjusted study-specific estimates into the random effects model showed a higher mean peak log₂-titer in men compared with women (absolute difference [men–women]: 0.32, 95% CI: 0.02–0.60). Fixed effects models controlling for study showed a similar result (log₂ ELISA titer, men–women: 0.34, 95% CI: 0.04–0.63). This equates to a geometric mean peak titer that is approximately 27% higher in men than women (95% CI: 3–55%). Peak log₂ PRNT titers were also higher (although not significantly) in men (men–women: 0.14, 95% CI: −0.30 to 0.58).ConclusionOur results show statistically significant differences in response to IMVAMUNE comparing healthy, vaccinia-naïve men with women and suggest that sex should be considered in further development and deployment of IMVAMUNE and other MVA-based vaccines.     

Eczema vaccinatum resulting from the transmission of vaccinia virus from a smallpox vaccinee: An investigation of potential fomites in the home environment

On March 3, 2007, a 2-year-old boy was hospitalized with eczema vaccinatum. His two siblings, one with eczema, were subsequently removed from the home. Swabs of household items obtained on March 13th were analyzed for orthopoxvirus DNA signatures with real-time PCR. Virus culture was attempted on positive specimens. Eight of 25 household samples were positive by PCR for orthopoxvirus; of these, three yielded viable vaccinia virus in culture. Both siblings were found to have serologic evidence of orthopoxvirus exposure. These findings have implications for smallpox preparedness, especially in situations where some household members are not candidates for vaccination.     

Genomic differences of Vaccinia virus clones from Dryvax smallpox vaccine: the Dryvax-like ACAM2000 and the mouse neurovirulent Clone-3

Conventional vaccines used for smallpox eradication were often denoted one or another strain of Vaccinia virus (VACV), even though seed virus was sub-cultured multifariously, which rendered the virion population genetically heterogeneous. ACAM2000 cell culture vaccine, recently licensed in the U.S., consists of a biologically vaccine-like VACV homogeneous-sequence clone from the conventional smallpox vaccine Dryvax, which we verified from Dryvax sequence chromatograms is genetically heterogeneous. ACAM2000 VACV and CL3, a mouse-neurovirulent clone from Dryvax, differ by 572 single nucleotide polymorphisms and 53 insertions–deletions of varied size, including a 4.5-kbp deletion in ACAM2000 and a 6.2-kbp deletion in CL3. The sequence diversity between the two clones precludes precisely defining why CL3 is more pathogenic; however, four genes appear significantly dissimilar to account for virulence differences. CL3 encodes intact immunomodulators interferon-/β and tumor necrosis factor receptors, which are truncated in ACAM2000. CL3 specifies a Cowpox and Variola virus-like ankyrin-repeat protein that might be associated with proteolysis via ubiquitination. And, CL3 shows an elongated thymidylate kinase, similar to the enzyme of the mouse-neurovirulent VACV-WR, a derivative of the New York City Board of Health vaccine, the origin vaccine of Dryvax. Although ACAM2000 encodes most proteins associated with immunization protection, the cloning probably delimited the variant epitopes and other motifs produced by Dryvax due to its VACV genetic heterogeneity. The sequence information for ACAM2000 and CL3 could be significant for resolving the dynamics of their different proteomes and thereby aid development of safer, more effective vaccines.     

The public acceptance of smallpox vaccination to fight bioterrorism in Japan: results of a large-scale opinion survey in Japan

Objectives  

This study examines the public acceptance of smallpox vaccinations in the event of a terrorist attack using smallpox. The article also provides public health professionals with the information necessary for such smallpox management.     

Contact transmission of vaccinia virus from smallpox vaccinees in the United States, 2003-2011

Since 2002, approximately 40,000 US civilians and 2.1 million military personnel have been vaccinated against smallpox. The vaccine contains live vaccinia virus that can be transferred through physical contact. This report summarizes numbers, rates, and characteristics of contact vaccinia cases that presented between December 2002 and March 2011. Cases were identified from reports in adverse event reporting systems and peer-reviewed literature. One hundred fifteen cases of vaccinia transmission through contact were identified (5.4 per 100,000 vaccinees); 52 reports (45%) noted laboratory confirmation. Three-quarters of vaccinees, but fewer than 8% of contact vaccinia cases, were described as military members. Most cases were household or intimate contacts (n = 86, 75%) or wrestling partners (n = 18, 16%) of vaccinees. Nearly all cases manifested mild, local skin reactions; of 14 hospitalized cases, one was life-threatening. Vaccinia transmission from vaccinees is relatively infrequent. Continued attention to both vaccinee education and screening for contraindications to vaccination is appropriate.     

Safety and immunogenicity of modified vaccinia Ankara as a smallpox vaccine in people with atopic dermatitis

Background

Following vaccination with traditional smallpox vaccines or after exposure to vaccinated individuals, subjects with atopic dermatitis (AD) can develop eczema vaccinatum, a severe disease with disseminated eruption of pustular contagious lesions. Alternative smallpox vaccines with an improved safety profile would address this unmet medical need.

Methods

An open-label controlled Phase I clinical trial was conducted to investigate the safety and immunogenicity of modified vaccinia Ankara (MVA) in 15 healthy subjects compared to 45 subjects with either mild allergic rhinitis, a history of AD or presenting with mild active AD. MVA was given (Week 0 and 4) by a subcutaneous injection during a 28-week observation period.

Results

No serious adverse event was reported and vaccinations with MVA did not lead to any clinically relevant skin reactions in AD subjects. Unsolicited administration site reactions did not show any trends compared to the healthy subject group. The majority of adverse reactions were mild to moderate, and all reactions were transient and resolved without intervention. The majority of vaccinees had seroconverted by ELISA (80–93%) and PRNT (69–79%) already two weeks after the first vaccination, increasing to 100% after the second immunization, with peak GMT above 1000 and 145 for ELISA and PRNT, respectively.

Conclusions

MVA was equally well tolerated and immunogenic in all enrolled subjects with mild to moderate pain and redness at the injection site being the most frequent adverse reactions. There were no differences in the safety or immunogenicity profile of MVA in healthy subjects or those with AD or allergic rhinitis. The study has confirmed MVA as a promising smallpox vaccine candidate and demonstrated in a small study population that the vaccine has a similar safety and immunogenicity profile in healthy subjects and people with active AD.Clinical trials registration: NCT00189917.     

Sexual orientation was associated with intention to be vaccinated with a smallpox vaccine against mpox: A cross-sectional preliminary survey in Japan

This survey aimed to assess the prevalence of intention to receive smallpox vaccine against mpox and its relationship with sexual orientation in Japan. A cross-sectional online survey was conducted in September-October 2022, with 12,900 assigned males and 13,413 assigned females participating. Modified Poisson regression analyses were performed to determine the relationship between vaccine willingness and sexual orientation, adjusting for socioeconomics, trust in government, COVID-19 vaccination status, and frequency of brothel visits. Vaccine willingness was higher in homosexual respondents than heterosexual counterparts, with proportions of 23.1 % among assigned males and 13.4 % among assigned females. Homosexual orientation was significantly associated with vaccine willingness, with prevalence ratios of 1.37 (95 % CI: 1.23–1.54) among assigned males and 1.34 (95 % CI: 1.13–1.59) among assigned females. These findings highlight the need for targeted vaccine promotion campaigns and ongoing monitoring of attitudes towards mpox and vaccine compliance in high-risk groups.     

Hepatitis B vaccination of relatives of hepatitis B virus DNA positive carriers: An experience with plasma-derived vaccine

We assessed in a western population the efficacy of a plasma-derived hepatitis B vaccine in relatives of highly infectious hepatitis B virus (HBV) carriers. A consecutive group of 103 HbsAg, anti-HBs and anti-HBc negative household relatives of 45 HBV-DNA positive chronic carriers received a 5 pg dose of plasma-derived vaccine at 0, 1, 2 and 12 months. Protective levels of immunity developed in 101 subjects (97.8%) 3 months after boosting. Low responders to the vaccine were mostly found among parents and spouses of carriers, whilst offspring and siblings were usually high responders. The main discriminant in predicting a good response was age below 12 years. Hyporesponsiveness did not occur in family clusters. No major HBV events occurred among immunized relatives patients. Hepatitis B vaccine is safe and effective in immunizing relatives of HBV carriers while no genetic conditioning of the immune response is evident among them.Corresponding author.     

Influenza vaccination in elderly residents in nursing homes: Immune response to trivalent and monovalent inactivated influenza virus vaccine in the season 1986–87

Immune responses to trivalent inactivated whole virus and monovalent subunit influenza vaccines, used in the season 1986–87, were analyzed in elderly residents in nursing homes. Higher levels of induced antibody were found in the group receiving two doses of trivalent vaccine. This suggests that high risk aged patients should receive a booster dose of vaccine annually. The antibody response to administration of supplemental vaccination, using monovalent subunit preparation, did not reach the high level of antibodies found following trivalent influenza vaccine.     

History of vaccine and immunization: Vaccine-hesitancy discussion in Germany in XIX century

Vaccination is the most celebrated and denigrated achievement of medicine and public health – not only today, but since Edward Jenner’s time (1798). In fact, the idea of injecting a mild form of “disease” into a healthy person was attacked even earlier than the discovery of vaccines. The forerunner of Jenner’s vaccination with bovine lymph was the inoculation of smallpox material from person to person, which, known in Europe since the beginning of the eighteenth century, was a target of harsh criticism. The reasons for criticizing the Jennerian vaccination and its mandatory practice were medical, anthropological, biological (vaccination is not safe), religious and ethical (it is wrong to inoculate a healthy person with disease), and political (vaccination is a threat to individual freedom). As such, anti-vaccination groups emerged in England, where inoculation was adopted early, as well as overall in Europe and in the United States. This paper focuses on the lesser known debate that arose in Germany in the years 1852–53 about the medical practice of vaccination. This is an a important topic of public health that has aroused a wide debate and comparison especially in recent years and now with pandemic on Sars-Cov-2 (Covid-19) and will probably be the subject of further reflection and consideration in the coming years.     

A randomized,double-blind,controlled clinical trial to evaluate the efficacy and safety of CJ-50300, a newly developed cell culture-derived smallpox vaccine,in healthy volunteers

A randomized, double-blind, controlled clinical trial was conducted to evaluate the efficacy and safety of CJ-50300, a newly developed cell culture-derived smallpox vaccine, and to determine its minimum effective dose. The overall rates of cutaneous “take” reaction and humoral and cellular immunogenicity in CJ-50300 vaccinees were 100% (123/123), 99.2% (122/123), and 90.8% (109/120), respectively, and these rates did not differ significantly between the conventional-dose and the low-dose CJ-50300 (1.0 × 10⁸ and 1.0 × 10⁷ plaque-forming units/mL, respectively) (P > 0.05 for each). No serious adverse reaction was observed. However, one case of possible generalized vaccinia occurred in the conventionally dosed group [ClinicalTrials.gov Identifier: NCT00607243].     

Systematic review of cost-effectiveness studies of human papillomavirus (HPV) vaccination: 9-Valent vaccine,gender-neutral and multiple age cohort vaccination

BackgroundThe success of human papillomavirus (HPV) national immunization program depends on effective strategies in optimizing the uptake of HPV vaccine. Given the increasing number of economic evaluations, this review was conducted to update the economic evidence on HPV vaccination, by focusing on: (i) 9-valent vaccine compared to bi- or quadrivalent vaccine; (ii) gender-neutral vaccination compared to female only vaccination; and (iii) multiple age cohort immunization compared to single age cohort immunization.MethodsSearches were performed until June 2016 using 4 databases: PubMed; Embase; Cochrane Library; and LILACS. The combined WHO, Drummond and CHEERS checklist were used to evaluate the quality of included studies.ResultsThirty-four studies were included in the review and most of them were conducted in high-income countries. The inclusion of adolescent boys in vaccination program was found to be cost-effective if vaccine price and coverage was low. When coverage for female was above 75%, gender-neutral vaccination was less cost-effective than when targeting only girls aged 9–18 years. Current evidence does not show conclusive proof of greater cost-effectiveness of 9-valent vaccine compared to the older HPV vaccines as the price for 9-valent vaccine was still uncertain. Multicohort immunization strategy was cost-effective in the age range 9–14 years but the upper age limit at which vaccination was no longer cost-effective needs to be further investigated. Key influential parameters identified were duration of vaccine protection, vaccine price, coverage, and discounting rates.ConclusionsThese findings are expected to support policy-makers in making recommendations for HPV immunization programs on either switching to the 9-valent vaccine or inclusion of adolescent boys’ vaccination or extending the age of vaccination.     

Improving influenza vaccination in chronically ill children using a tertiary-care based vaccination clinic: Is there a role for the live-attenuated influenza vaccine (LAIV)?

BackgroundChildren with underlying medical conditions should receive influenza vaccine (IV) yearly; yet this remains sub-optimal. We aimed to describe our experience with a tertiary-care hospital-based influenza vaccination clinic for this at-risk population.MethodsFrom October to December 2012, 2013, and 2014, we ran an influenza vaccination clinic at the Montreal Children's Hospital, where children with high-risk conditions come for their follow-up. Both injectable IV (IIV) and live-attenuated IV (LAIV) were offered free of charge to patients and their household contacts. Upon vaccination, parents were asked to fill a pre-piloted questionnaire.ResultsWe vaccinated a total of 2640 high-risk children and 1912 household members during the three influenza vaccination seasons. In 2012 and 2013, 631 and 630 patients with chronic illnesses were vaccinated, compared to 1379 in 2014. Caregivers preferred LAIV primarily because no needle was involved (49.0%) and because it was perceived as less painful (46.9%). LAIV was administered to 69% (2012), 55% (2013) and 47% (2014) of high-risk children. The main reason for not receiving LAIV was because it was contra-indicated. A small fraction of children previously vaccinated with LAIV who did not present any contraindication to LAIV opted for IIV: 12/101 (11.8%) in 2013 and 16/272 (5.9%) in 2014. In 2014, this was mainly due to a previous negative experience with LAIV (11/16).ConclusionHaving an influenza vaccination clinic on site at a tertiary care hospital, where children come for their scheduled visits, facilitates yearly influenza vaccination in children with chronic illnesses. LAIV is preferred by caregivers and patients, when not contraindicated.     

The cost-effectiveness of influenza vaccination in elderly Australians: An exploratory analysis of the vaccine efficacy required

It is important to consider the value for money offered by existing elderly influenza vaccination programs, particularly as doubts persist about the magnitude of the effectiveness of such programs. An informative approach to explore the value of vaccination is to consider what vaccine efficacy would be required for a program to be considered cost-effective. To estimate the cost-effectiveness of the current elderly (65+ years) influenza vaccination program in Australia, we modelled how the hypothetical removal of vaccination would increase current disease burden estimates depending on alternative vaccine efficacy assumptions. The base-case results of the analysis found that the existing elderly vaccination program is likely to be cost-effective (under A$50,000 per quality-adjusted life year gained) if the vaccine efficacy is above ∼30%. This study offers reassurance that the influenza vaccination of elderly Australians is likely to offer value for money.     

Seasonal influenza vaccine dose distribution in 195 countries (2004–2013): Little progress in estimated global vaccination coverage

Seasonal influenza is an important disease which results in 250,000–500,000 annual deaths worldwide. Global targets for vaccination coverage rates (VCRs) in high-risk groups are at least 75% in adults ≥65 years and increased coverage in other risk groups. The International Federation of Pharmaceutical Manufacturers and Associations Influenza Vaccine Supply (IFPMA IVS) International Task Force developed a survey methodology in 2008, to assess the global distribution of influenza vaccine doses as a proxy for VCRs. This paper updates the previous survey results on absolute numbers of influenza vaccine doses distributed between 2004 and 2013 inclusive, and dose distribution rates per 1000 population, and provides a qualitative assessment of the principal enablers and barriers to seasonal influenza vaccination. The two main findings from the quantitative portion of the survey are the continued negative trend for dose distribution in the EURO region and the perpetuation of appreciable differences in scale of dose distribution between WHO regions, with no observed convergence in the rates of doses distributed per 1000 population over time. The main findings from the qualitative portion of the survey were that actively managing the vaccination program in real-time and ensuring political commitment to vaccination are important enablers of vaccination, whereas insufficient access to vaccination and lack of political commitment to seasonal influenza vaccination programs are likely contributing to vaccination target failures. In all regions of the world, seasonal influenza vaccination is underutilized as a public health tool. The survey provides evidence of lost opportunity to protect populations against potentially serious influenza-associated disease. We call on the national and international public health communities to re-evaluate their political commitment to the prevention of the annual influenza disease burden and to develop a systematic approach to improve vaccine distribution equitably.