Evidence for Residual Immunity to Smallpox After Vaccination and Implications for Re-emergence.

INTRODUCTION: Smallpox has been eradicated but advances in synthetic biology have increased the risk of its re-emergence. Residual immunity in individuals who were previously vaccinated may mitigate the impact of an outbreak, but there is a high degree of uncertainty about the duration and degree of residual immunity. Both cell-mediated and humoral immunity are thought to be important but the exact mechanisms of protection are unclear. Guidelines usually suggest vaccine-induced immunity wanes to zero after 3-10 years post vaccination, whereas other estimates show long term immunity over decades. MATERIALS AND METHODS: A systematic review of the literature was conducted to quantify the duration and extent of residual immunity to smallpox after vaccination. RESULTS: Twenty-nine papers related to quantifying residual immunity to smallpox after vaccination were identified: neutralizing antibody levels were used as immune correlates of protection in 11/16 retrospective cross-sectional studies, 2/3 epidemiological studies, 6/7 prospective vaccine trials and 0/3 modeling studies. Duration of protection of >20 years was consistently shown in the 16 retrospective cross-sectional studies, while the lowest estimated duration of protection was 11.7 years among the modeling studies. Childhood vaccination conferred longer duration of protection than vaccination in adulthood, and multiple vaccinations did not appear to improve immunity. CONCLUSIONS: Most studies suggest a longer duration of residual immunity (at least 20 years) than assumed in smallpox guidelines. Estimates from modeling studies were less but still greater than the 3-10 years suggested by the WHO Committee on International Quarantine or US CDC guidelines. These recommendations were probably based on observations and studies conducted while smallpox was endemic. The cut-off values for pre-existing antibody levels of >1:20 and >1:32 reported during the period of endemic smallpox circulation may not be relevant to the contemporary population, but have been used as a threshold for identifying people with residual immunity in post-eradication era studies. Of the total antibodies produced in response to smallpox vaccination, neutralizing antibodies have shown to contribute significantly to immunological memory. Although the mechanism of immunological memory and boosting is unclear, revaccination is likely to result in a more robust response. There is a need to improve the evidence base for estimates on residual immunity to better inform planning and preparedness for re-emergent smallpox.

Immunogenicity and safety of three consecutive production lots of the non replicating smallpox vaccine MVA: A randomised, double blind, placebo controlled phase III trial.

BACKGROUND: Modified Vaccinia Ankara (MVA) is a live, viral vaccine under advanced development as a non-replicating smallpox vaccine. A randomised, double-blind, placebo-controlled phase III clinical trial was conducted to demonstrate the humoral immunogenic equivalence of three consecutively manufactured MVA production lots, and to confirm the safety and tolerability of MVA focusing on cardiac readouts. METHODS: The trial was conducted at 34 sites in the US. Vaccinia-naïve adults aged 18-40 years were randomly allocated to one of four groups using a 1:1:1:1 randomization scheme. Subjects received either two MVA injections from three consecutive lots (Groups 1-3), or two placebo injections (Group 4), four weeks apart. Everyone except personnel involved in vaccine handling and administration was blinded to treatment. Safety assessment focused on cardiac monitoring throughout the trial. Vaccinia-specific antibody titers were measured using a Plaque Reduction Neutralization Test (PRNT) and an Enzyme-Linked Immunosorbent Assay (ELISA). The primary immunogenicity endpoint was Geometric Mean Titers (GMTs) after two MVA vaccinations measured by PRNT at trial visit 4. This trial is registered with ClinicalTrials.gov, number NCT01144637. RESULTS: Between March 2013 and May 2014, 4005 subjects were enrolled and received at least one injection of MVA (n = 3003) or placebo (n = 1002). The three MVA lots induced equivalent antibody titers two weeks after the second vaccination, with seroconversion rates of 99·8% (PRNT) and 99·7% (ELISA). Overall, 180 (6·0%) subjects receiving MVA and 29 (2·9%) subjects in the placebo group reported at least one unsolicited Adverse Event (AE) that was considered trial-related. Vaccination was well tolerated without significant safety concerns, particularly regarding cardiac assessment. CONCLUSIONS: The neutralizing and total antibody titers induced by each of the three lots were equivalent. No significant safety concerns emerged in this healthy trial population, especially regarding cardiac safety, thus confirming the excellent safety and tolerability profile of MVA. TRIAL REGISTRATION: ClinicalTrials.gov NCT01144637.

Freeze-dried live attenuated smallpox vaccine prepared in cell culture "LC16-KAKETSUKEN": Post-marketing surveillance study on safety and efficacy compliant with Good Clinical Practice.

BACKGROUND: In Japan, production of smallpox vaccine LC16m8 (named LC16-KAKETSUKEN) was restarted and was determined to be maintained as a national stockpile in March 2002. OBJECTIVE: To conduct a post-marketing surveillance study of the vaccination of freeze-dried live attenuated smallpox vaccine prepared in cell culture LC16-KAKETSUKEN using attenuated vaccinia strain LC16m8. The study complied with Good Clinical Practice, focusing on a comparison between primary vaccinees and re-vaccinees. METHOD: 268 personnel (261 males and 7 females) of the Japan Ground Self-Defense Force were inoculated with LC16-KAKETSUKEN and thereafter adverse events and efficacy were evaluated. RESULTS: Among 268 vaccinee participants, the following vaccinees showed adverse events, none serious: 53 of 196 primary vaccinees (without previous smallpox vaccination), 4 of 71 re-vaccinees (with previous smallpox vaccination) and 1 vaccinee with unknown previous vaccination history. A breakdown of adverse events observed in this study (total 268 vaccinees) showed the following minor or mild adverse events: 52 (19.4%) swelling of axillary lymph node, 4 (1.5%) fever, 2 (0.7%) fatigue, 1 (0.4%) of rash, 14 (5.2%) erythema at the inoculation site, 1 (0.4%) swelling at the inoculation site and 1 (0.4%) autoinoculation. The incidence of adverse events for primary vaccinees (53/196; 27.0%) was significantly higher than for re-vaccinees (4/71; 5.6%). However, the proportion of vaccine take was significantly higher for primary vaccinees (185/196; 94.4%) than for re-vaccinees (58/71; 81.7%). Although the proportion of vaccine take of re-vaccinees was significantly lower than for primary vaccinees due to preexisting immunity by previous vaccination, no significant difference was found in neutralizing antibody titers between primary vaccinees and re-vaccinees at 1, 4 and 7 months after LC16-KAKETSUKEN vaccination. CONCLUSION: The present post-marketing surveillance study compliant with Good Clinical Practice demonstrated the efficacy and safety of the smallpox vaccine LC16-KAKETSUKEN in an adult population. LC16-KAKETSUKEN is the sole currently available licensed smallpox vaccine for both adult and pediatric populations.

A Multicenter, Open-Label, Controlled Phase II Study to Evaluate Safety and Immunogenicity of MVA Smallpox Vaccine (IMVAMUNE) in 18-40 Year Old Subjects with Diagnosed Atopic Dermatitis.

BACKGROUND: Replicating smallpox vaccines can cause severe complications in individuals with atopic dermatitis (AD). Prior studies evaluating Modified Vaccinia Ankara virus (MVA), a non-replicating vaccine in humans, showed a favorable safety and immunogenicity profile in healthy volunteers. OBJECTIVE: This Phase II study compared the safety and immunogenicity of MVA enrolling groups of 350 subjects with AD (SCORAD ≤ 30) and 282 healthy subjects. METHODS: Subjects were vaccinated twice with MVA, each dose given subcutaneously 4 weeks apart. Adverse events, cardiac parameters, and the development of vaccinia virus humoral immune responses were monitored. RESULTS: The overall safety of the vaccine was similar in both groups. Adverse events affecting skin were experienced significantly more often in subjects with AD, but the majority of these events were mild to moderate in intensity. Seroconversion rates and geometric mean titers for total and neutralizing vaccinia-specific antibodies in the AD group were non-inferior compared to the healthy subjects. LIMITATIONS: The size of the study population limited the detection of serious adverse events occurring at a frequency less than 1%. CONCLUSION: MVA has a favorable safety profile and the ability to elicit vaccinia-specific immune responses in subjects with AD. TRIAL REGISTRATION: ClinicalTrials.gov NCT00316602.

Vaccinia virus infections in martial arts gym, Maryland, USA, 2008.

Vaccinia virus is an orthopoxvirus used in the live vaccine against smallpox. Vaccinia virus infections can be transmissible and can cause severe complications in those with weakened immune systems. We report on a cluster of 4 cases of vaccinia virus infection in Maryland, USA, likely acquired at a martial arts gym.

Monitoring the safety of a smallpox vaccination program in the United States: report of the joint Smallpox Vaccine Safety Working Group of the advisory committee on immunization practices and the Armed Forces Epidemiological Board.

In December 2002, the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices and the Department of Defense Armed Forces Epidemiological Board formed a joint Smallpox Vaccine Safety Working Group (SVS WG) to provide independent safety oversight for smallpox vaccination safety-monitoring systems. From January 2003 through June 2004, the SVS WG reviewed individual and aggregate safety data on postvaccination adverse events. Serious adverse events were rare because of careful education, prevaccination screening, and strict attention to vaccination-site management. Recent vaccinees safely cared for high-risk patients, adhering to recommended site care. Human immunodeficiency virus-infected individuals without severe immunosuppression had uncomplicated vaccination reactions. Epidemiological studies supported a causal relationship between myocarditis and/or pericarditis and smallpox vaccination. Data supported neutrality regarding hypothesized causal associations between vaccination and dilated cardiomyopathy or ischemic cardiac disease. The SVS WG concurs with recommendations to defer from vaccination any person with >/=3 ischemic cardiac disease risk factors.

[4647-cell culture for preparation of recombinant bivaccine against smallpox and hepatitis B].

The seeding and working banks of a 4647-cell culture have been created. The 4647-cell culture in these banks has a high proliferative activity, as well as the morphology, typical of this line, and the karyotype and the enzymogram, which are characteristic for the cells of an African talapoin (Cercopithecus aethiops). The culture is not contaminated with bacteria, fungi, Mycoplasma, and viruses, including oncoviruses. The deposited 4647 cells have high viral productive properties for the accumulation of the recombinant virus strain b7,5S2-S vaccine and keep the stability of all biological properties during a long-term cultivation. The continuous 4647 cell line was tested at the L. A. Tarasevich State Institute of SK. The seeding and working banks of 4647-cell culture at passages 108 and 128 are recommended as a substrate for cultivation of the strain b7,5S2-S vaccinia, used to prepare a bivaccine against smallpox and hepatitis B.

Public health nurses' views on voluntary smallpox vaccination.

Between January and June 2003, voluntary smallpox vaccination of healthcare workers and mandatory vaccination of military personnel was an important public health topic. This paper discusses the attitudes of nurses from two county public health departments in an upper-Midwestern state who were asked to volunteer to take the smallpox vaccine and to prepare to assist in the operation of possible mass immunization clinics. The responses of these healthcare professionals are compared to those of physicians and the general public. The public health nurses in this sample were less likely to view smallpox as a potential biological weapon than was the general public or other healthcare workers studied previously.

[Smallpox--historical or real threat]. / Ospa prawdziwa--stare czy nowe zagrozenie?

Presently, there is no real possibility of natural re-emergence of smallpox virus, which was eradicated globally more then 25 years ago. During the last decade the possibility of use of smallpox virus as a biological weapon by a criminal organisation was emphasised. The re-emergence of smallpox virus would lead to unprecedented disaster. Theoretical models indicated that only extremely strict and enforced interventions could stop the spread of epidemic, but the assumptions of these models were unrealistic. Presently, there are limited stocks of the first generation smallpox vaccine left in the world. This vaccine, as well as the second-generation vaccine are associated with multiple adverse events, including fatalities and may not be accepted by society. Much safer vaccines are now being developed. Strategic plan of prophylactic vaccinations requires defining the groups to be immunised in the first place and whether immunisation should start before or after a first smallpox case would occur.

New generation of cell culture assay for smallpox vaccine potency.

The potency of smallpox vaccines produced in the 1970s was tested by titration onto chorioallantoic membranes of fertilized hen eggs (CAM assay). The potency specification commonly approved for these vaccines was a titer above 10(8) pock-forming units per milliliter. We developed and validated a cell culture titration assay to have a more reliable potency test. The cell titration assay and the CAM assay were tested in parallel on 34 first-generation smallpox vaccine lots. These allowed us to demonstrate that a correlation does exist between the two titration techniques and to determine a new in-house specification for the cell titration method. This in vitro potency assay will allow us to test first-generation smallpox vaccines produced on the skin of living animals but will also give a hint of the potency specification that should be assigned for new generations of cell-derived smallpox vaccines.

Smallpox vaccination and bioterrorism with pox viruses.

Bioterrorist attacks occupy a special place amongst the innumerable potential types of terrorist attack, with the intentional release of pox viruses being especially feared in this connection. Apart from the variola virus, the agent responsible for smallpox in humans, the monkeypox virus and numerous other animal pox viruses pose potential risks for humans and animals. This risk scenario also includes recombinations between the various pox viruses, changes in hosts and genetically engineered manipulations of pox viruses. For over 200 years, the method of choice for combatting smallpox was via vaccination with a reproductive, original vaccinia virus. Worldwide eradication of smallpox at the end of the 1970s and the discontinuation of routine smallpox vaccination in 1980 can be credited to such vaccination. Unfortunately, these vaccinations were associated with a large number of postvaccinal impairments, sometimes resulting in death (e.g. postvaccinal encephalitis). The only way to restrict such postvaccinal complications was to carry out initial vaccination within the first 2 postnatal years. Initial vaccination at a later age led to such a sharp increase in the number of vaccines with complications that vaccination had to be discouraged. The dilemma of the smallpox vaccine stocks stems from the fact that a large portion of these stocks are produced with the same vaccinia strains as before. This is irresponsible, especially as the percentage of immune-suppressed persons in the population, for whom vaccination-related complications pose an especial threat, is increasing. One solution to the dilemma of the smallpox vaccine stocks is the MVA strain. It is harmless, protects humans and animals equally well against smallpox and can be applied parenterally.

The new cell culture smallpox vaccine should be offered to the general population.

A series of major factors must be weighed in deciding whether or not, and to what extent, a particular country should consider pre-exposure vaccination for smallpox. These include the risk of a bioterrorist attack using smallpox, the risk of secondary spread from another country, the risks and benefits of vaccination, the effectivenes s of vaccination pre- and post-exposure, the prevalence of immunocompromised persons, the capacity of the medical care delivery system and the wealth of a nation. We review here the issues and variables relevant for policy making, propose a framework for country-specific decision making and suggest the World Health Organization has a key role to play, particularly with regard to lower-income countries. In doing so, we support the proposition.

The new cell culture smallpox vaccine should not be offered to the general population.

Cell based smallpox vaccines are to be welcomed, but any decision to vaccinate whole populations must await firstly better intelligence about the gravity of the threat from bioterrorists, including their ability to release smallpox in such a way that wide dissemination could take place; secondly evidence that vaccines grown in cell culture are protective and safe; and thirdly that the vaccines would be generally acceptable and their introduction would not compromise the rest of national immunisation programmes. Smallpox vaccination should not be offered to the general population until these uncertainties have been resolved, by which time bioterrorism might possibly have been overcome or the development of antiviral treatment might have made renewed smallpox vaccination unnecessary. Meanwhile, preparations for rapid deployment of the historically well-tried containment measures at the epicentres of any smallpox release should proceed, their effectiveness should be tested, and their adequacy kept under review.