The moral importance of selecting people randomly

This article discusses some ethical principles for distributing pandemic influenza vaccine and other indivisible goods. I argue that a number of principles for distributing pandemic influenza vaccine recently adopted by several national governments are morally unacceptable because they put too much emphasis on utilitarian considerations, such as the ability of the individual to contribute to society. Instead, it would be better to distribute vaccine by setting up a lottery. The argument for this view is based on a purely consequentialist account of morality; i.e. an action is right if and only if its outcome is optimal. However, unlike utilitarians I do not believe that alternatives should be ranked strictly according to the amount of happiness or preference satisfaction they bring about. Even a mere chance to get some vaccine matters morally, even if it is never realized.     

Removing barriers to global pandemic influenza vaccination

This article clarifies the regulatory issues surrounding influenza pandemic vaccine for the larger policy community and describes the need for regulatory harmonization. Vaccination would save lives in an influenza pandemic, but a lack of global manufacturing capacity will leave most of the world without access to vaccine. Capacity can be expanded if governments harmonize their regulatory policies. This article details the regulatory approaches taken by the United States, the European Union, and Japan for pandemic vaccine development, three regions that produce the majority of the world's seasonal influenza vaccine. They should quickly converge on regulatory requirements, intellectual property considerations, the use of recombinant DNA techniques for vaccine production, and technical issues about the composition of pandemic vaccine.     

Public health strategies for distribution of influenza vaccine during an influenza pandemic

In order to consider the ethical issues around vaccine distribution during an influenza pandemic, it is critical to have an understanding of the role of influenza vaccine in a pandemic, the rate at which vaccine is likely to be come available, who will likely produce and "own" the vaccine, how vaccine distribution and administration might be accomplished, and which are the groups that might be deemed highest priority to be vaccinated against influenza. The United States and Connecticut have been considering the more challenging of these issues and have learned from Canada, which previously discussed and made decisions on the challenges related to vaccine distribution. Although there is still some critical advance thinking that needs to be done, planning for the response to an influenza pandemic is now at an advanced stage. The keys to preparedness at this stage are to be aware of the vaccine distribution options, to know the benefits and limitations of each option, and to be flexible but nimble in dealing with a real pandemic.     

Perspectives on antiviral use during pandemic influenza.

Antiviral agents could potentially play a major role in the initial response to pandemic influenza, particularly with the likelihood that an effective vaccine is unavailable, by reducing morbidity and mortality. The M2 inhibitors are partially effective for chemoprophylaxis of pandemic influenza and evidence from studies of interpandemic influenza indicate that the neuraminidase inhibitors would be effective in prevention. In addition to the symptom benefit observed with M2 inhibitor treatment, early therapeutic use of neuraminidase inhibitors has been shown to reduce the risk of lower respiratory complications. Clinical pharmacology and adverse drug effect profiles indicate that the neuraminidase inhibitors and rimantadine are preferable to amantadine with regard to the need for individual prescribing and tolerance monitoring. Transmission of drug-resistant virus could substantially limit the effectiveness of M2 inhibitors and the possibility exists for primary M2 inhibitor resistance in a pandemic strain. The frequency of resistance emergence is lower with neuraminidase inhibitors and mathematical modelling studies indicate that the reduced transmissibility of drug-resistant virus observed with neuraminidase inhibitor-resistant variants would lead to negligible community spread of such variants. Thus, there are antiviral drugs currently available that hold considerable promise for response to pandemic influenza before a vaccine is available, although considerable work remains in realizing this potential. Markedly increasing the quantity of available antiviral agents through mechanisms such as stockpiling, educating health care providers and the public and developing effective means of rapid distribution to those in need are essential in developing an effective response, but remain currently unresolved problems.     

Developing vaccines against pandemic influenza.

Pandemic influenza presents special problems for vaccine development. There must be a balance between rapid availability of vaccine and the safeguards to ensure safety, quality and efficacy of vaccine. Vaccine was developed for the pandemics of 1957, 1968, 1977 and for the pandemic alert of 1976. This experience is compared with that gained in developing vaccines for a possible H5N1 pandemic in 1997-1998. Our ability to mass produce influenza vaccines against a pandemic threat was well illustrated by the production of over 150 million doses of 'swine flu' vaccine in the USA within a 3 month period in 1976. However, there is cause for concern that the lead time to begin vaccine production is likely to be about 7-8 months. Attempts to reduce this time should receive urgent attention. Immunogenicity of vaccines in pandemic situations is compared over the period 1968-1998. A consistent feature of the vaccine trials is the demonstration that one conventional 15 microg haemagglutinin dose of vaccine is not sufficiently immunogenic in naive individuals. Much larger doses or two lower doses are needed to induce satisfactory immunity. There is some evidence that whole-virus vaccines are more immunogenic than split or subunit vaccines, but this needs substantiating by further studies. H5 vaccines appeared to be particularly poor immunogens and there is evidence that an adjuvant may be needed. Prospects for improving the development of pandemic vaccines are discussed.     

Modelling the Transmission Dynamics and Control of the Novel 2009 Swine Influenza (H1N1) Pandemic

The paper presents a deterministic compartmental model for the transmission dynamics of swine influenza (H1N1) pandemic in a population in the presence of an imperfect vaccine and use of drug therapy for confirmed cases. Rigorous analysis of the model, which stratifies the infected population in terms of their risk of developing severe illness, reveals that it exhibits a vaccine-induced backward bifurcation when the associated reproduction number is less than unity. The epidemiological consequence of this result is that the effective control of H1N1, when the reproduction number is less than unity, in the population would then be dependent on the initial sizes of the subpopulations of the model. For the case where the vaccine is perfect, it is shown that having the reproduction number less than unity is necessary and sufficient for effective control of H1N1 in the population (in such a case, the associated disease-free equilibrium is globally asymptotically stable). The model has a unique endemic equilibrium when the reproduction number exceeds unity. Numerical simulations of the model, using data relevant to the province of Manitoba, Canada, show that it reasonably mimics the observed H1N1 pandemic data for Manitoba during the first (Spring) wave of the pandemic. Further, it is shown that the timely implementation of a mass vaccination program together with the size of the Manitoban population that have preexisting infection-acquired immunity (from the first wave) are crucial to the magnitude of the expected burden of disease associated with the second wave of the H1N1 pandemic. With an estimated vaccine efficacy of approximately 80%, it is projected that at least 60% of Manitobans need to be vaccinated in order for the effective control or elimination of the H1N1 pandemic in the province to be feasible. Finally, it is shown that the burden of the second wave of H1N1 is expected to be at least three times that of the first wave, and that the second wave would last until the end of January or early February, 2010.     

The importance of naturally attenuated SARS-CoV-2in the fight against COVID-19

The current SARS-CoV-2 pandemic is wreaking havoc throughout the world and has rapidly become a global health emergency. A central question concerning COVID-19 is why some individuals become sick and others not. Many have pointed already at variation in risk factors between individuals. However, the variable outcome of SARS-CoV-2 infections may, at least in part, be due also to differences between the viral subspecies with which individuals are infected. A more pertinent question is how we are to overcome the current pandemic. A vaccine against SARS-CoV-2 would offer significant relief, although vaccine developers have warned that design, testing and production of vaccines may take a year if not longer. Vaccines are based on a handful of different designs (i), but the earliest vaccines were based on the live, attenuated virus. As has been the case for other viruses during earlier pandemics, SARS-CoV-2 will mutate and may naturally attenuate over time (ii). What makes the current pandemic unique is that, thanks to state-of-the-art nucleic acid sequencing technologies, we can follow in detail how SARS-CoV-2 evolves while it spreads. We argue that knowledge of naturally emerging attenuated SARS-CoV-2 variants across the globe should be of key interest in our fight against the pandemic.     

Economic Analysis of Pandemic Influenza Vaccination Strategies in Singapore

Background

All influenza pandemic plans advocate pandemic vaccination. However, few studies have evaluated the cost-effectiveness of different vaccination strategies. This paper compares the economic outcomes of vaccination compared with treatment with antiviral agents alone, in Singapore.

Methodology

We analyzed the economic outcomes of pandemic vaccination (immediate vaccination and vaccine stockpiling) compared with treatment-only in Singapore using a decision-based model to perform cost-benefit and cost-effectiveness analyses. We also explored the annual insurance premium (willingness to pay) depending on the perceived risk of the next pandemic occurring.

Principal Findings

The treatment-only strategy resulted in 690 deaths, 13,950 hospitalization days, and economic cost of USD$497 million. For immediate vaccination, at vaccine effectiveness of >55%, vaccination was cost-beneficial over treatment-only. Vaccine stockpiling is not cost-effective in most scenarios even with 100% vaccine effectiveness. The annual insurance premium was highest with immediate vaccination, and was lower with increased duration to the next pandemic. The premium was also higher with higher vaccine effectiveness, attack rates, and case-fatality rates. Stockpiling with case-fatality rates of 0.4–0.6% would be cost-beneficial if vaccine effectiveness was >80%; while at case-fatality of >5% stockpiling would be cost-beneficial even if vaccine effectiveness was 20%. High-risk sub-groups warrant higher premiums than low-risk sub-groups.

Conclusions

The actual pandemic vaccine effectiveness and lead time is unknown. Vaccine strategy should be based on perception of severity. Immediate vaccination is most cost-effective, but requires vaccines to be available when required. Vaccine stockpiling as insurance against worst-case scenarios is also cost-effective. Research and development is therefore critical to develop and stockpile cheap, readily available effective vaccines.     

From lethal virus to life-saving vaccine: developing inactivated vaccines for pandemic influenza

Over the past eight years, cases of human infection with highly pathogenic avian influenza viruses have raised international concern that we could be on the brink of a global influenza pandemic. Many of these human infections have proved fatal and if the viruses had been able to transmit efficiently from person to person, the effects would have been devastating. How can we arm ourselves against this pandemic threat when these viruses are too dangerous to use in conventional vaccine production? Recent technological developments (reverse genetics) have allowed us to manipulate the influenza virus genome so that we can construct safe, high-yielding vaccine strains. However, the transition of reverse-genetic technologies from the research laboratory to the manufacturing environment has presented new challenges for vaccine manufacturers as well as veterinary and public health authorities.     

Effect of prior vaccination with a seasonal trivalent influenza vaccine on the antibody response to the influenza pandemic H1N1 2009 vaccine: a randomized controlled trial

Vaccination with the non-adjuvanted split-virion A/California/7/2009 influenza vaccine (pandemic H1N1 2009 vaccine) began in October 2009 in Japan. The present study was designed to assess the effect of prior vaccination with a seasonal trivalent influenza vaccine on the antibody response to the pandemic H1N1 2009 vaccine in healthy adult volunteers. One hundred and seventeen participants aged 22 to 62 were randomly assigned to two study groups. In Group 1 (the priming group), participants were first vaccinated with the seasonal trivalent influenza vaccine followed by two separate one-dose vaccinations of the pandemic H1N1 2009 vaccine, whereas in Group 2 (the non-priming group), the participants were first vaccinated with one dose of the pandemic H1N1 2009 vaccine, followed by simultaneous vaccination of the seasonal trivalent vaccine and the second dose of the pandemic H1N1 2009 vaccine. The participants in Group 2 had a seroprotection rate (SPR) of 79.7% and a seroconversion rate (SCR) of 79.7% in the hemagglutination-inhibition test after the first dose of the pandemic H1N1 2009 vaccine, indicating that the pandemic H1N1 2009 vaccine is sufficiently immunogenic. On the other hand, the participants of Group 1 had a significantly weaker antibody response, with a SPR of 60.8% and a SCR of 58.5%. These results indicate that prior vaccination with the seasonal trivalent influenza vaccine inhibits the antibody response to the pandemic H1N1 2009 vaccine. Therefore, the pandemic H1N1 2009 vaccine should be administered prior to vaccination with the seasonal trivalent influenza vaccine.     

A simple Pichia pastoris fermentation and downstream processing strategy for making recombinant pandemic Swine Origin Influenza A virus Hemagglutinin protein

The present Influenza vaccine manufacturing process has posed a clear impediment to initiation of rapid mass vaccination against spreading pandemic influenza. New vaccine strategies are therefore needed that can accelerate the vaccine production. Pichia offers several advantages for rapid and economical bulk production of recombinant proteins and, hence, can be attractive alternative for producing an effective influenza HA based subunit vaccine. The recombinant Pichia harboring the transgene was subjected to fed-batch fermentation at 10 L scale. A simple fermentation and downstream processing strategy is developed for high-yield secretory expression of the recombinant Hemagglutinin protein of pandemic Swine Origin Influenza A virus using Pichia pastoris via fed-batch fermentation. Expression and purification were optimized and the expressed recombinant Hemagglutinin protein was verified by sodium dodecyl sulfate polyacrylamide gel electrophoresis, Western blot and MALDI-TOF analysis. In this paper, we describe a fed-batch fermentation protocol for the secreted production of Swine Influenza A Hemagglutinin protein in the P. pastoris GS115 strain. We have shown that there is a clear relationship between product yield and specific growth rate. The fed-batch fermentation and downstream processing methods optimized in the present study have immense practical application for high-level production of the recombinant H1N1 HA protein in a cost effective way using P. pastoris.     

Pandemic influenza: overview of vaccines and antiviral drugs

Pandemic influenza has become a high priority item for all public health authorities. An influenza pandemic is believed to be imminent, and scientists agree that it will be a matter of when, where, and what will be the causative agent. Recently, most attention has been directed to human cases of avian influenza caused by a H5N1 avian influenza virus. An effective vaccine will be needed to substantially reduce the impact of an influenza pandemic. Current influenza vaccine manufacturing technology is not adequate to support vaccine production in the event of an avian influenza outbreak, and it has now become clear that new innovative production technology is required. Antiviral drugs, on the other hand, can play a very important role in slowing the disease spread but are in short supply and resistance has been a major issue. Here, we provide an update on the status of pandemic vaccine development and antiviral drugs. Finally, we conclude with some proposed areas of focus in pandemic vaccine preparedness.     

Monitoring vaccine safety during an influenza pandemic

In the event that a vaccine is available during an influenza pandemic, vaccine safety monitoring will occur as part of comprehensive public health surveillance of the vaccination campaign. Though inactivated influenza vaccines have been widely used in the United States and much is known about their safety profile, attention will need to be paid to both common self-limited adverse reactions and rarer, more serious events that may or may not be causally related to vaccination. The primary surveillance systems used to generate and test hypotheses about vaccine safety concerns are the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink (VSD), respectively. Examples of recent use of these systems to investigate influenza vaccine safety and enhancements planned for use during a pandemic are presented. Ethical issues that will need to be addressed as part of an overall vaccine safety response include risk communication and injury compensation. Advance planning and the use of available technologic solutions are needed to respond to the scientific and logistic challenges involved in safely implementing mass vaccination during a pandemic.     

Intent to Receive Pandemic Influenza A (H1N1) Vaccine,Compliance with Social Distancing and Sources of Information in NC, 2009

Background

Public adherence to influenza vaccination recommendations has been low, particularly among younger adults and children under 2, despite the availability of safe and effective seasonal vaccine. Intention to receive 2009 pandemic influenza A (H1N1) vaccine has been estimated to be 50% in select populations. This report measures knowledge of and intention to receive pandemic vaccine in a population-based setting, including target groups for seasonal and H1N1 influenza.

Methodology and Principal Findings

On August 28–29, 2009, we conducted a population-based survey in 2 counties in North Carolina. The survey used the 30×7 two-stage cluster sampling methodology to identify 210 target households. Prevalence ratios (PR) and 95% confidence intervals (CI) were estimated. Knowledge of pandemic influenza A (H1N1) vaccine was high, with 165 (80%) aware that a vaccine was being prepared. A total of 133 (64%) respondents intended to receive pandemic vaccine, 134 (64%) intended to receive seasonal vaccine, and 109 (53%) intended to receive both. Reporting great concern about H1N1 infection (PR 1.55; 95%CI: 1.30, 1.85), receiving seasonal influenza vaccine in 2008–09 (PR 1.47; 95%CI: 1.18, 1.82), and intending to receive seasonal influenza vaccine in 2009–10 (PR 1.27; 95%CI: 1.14, 1.42) were associated with intention to receive pandemic vaccine. Not associated were knowledge of vaccine, employment, having children under age 18, gender, race/ethnicity and age. Reasons cited for not intending to get vaccinated include not being at risk for infection, concerns about vaccine side effects and belief that illness caused by pandemic H1N1 would be mild. Forty-five percent of households with children under 18 and 65% of working adults reported ability to comply with self-isolation at home for 7–10 days if recommended by authorities.

Conclusions and Significance

This is the first report of a population based rapid assessment used to assess knowledge and intent to receive pandemic vaccine in a community sample. Intention to receive pandemic and seasonal vaccines was higher than previously published reports. To reach persons not intending to receive pandemic vaccine, public health communications should focus on the perceived risk of infection and concerns about vaccine safety.     

Preliminary study about sublingual administration of bacteria-expressed pandemic H1N1 influenza vaccine in miniature pigs

Sublingual (SL) administration of influenza vaccine would be non-invasive and effective way to give human populations protective immunity against the virus, especially when pandemic influenza outbreaks. In this study, the efficacy of pandemic influenza virus-based subunit vaccines was tested after sublingual (SL) adjuvant administration in pigs. Eight specific pathogen-free Yucatan pigs were divided into 4 groups: nonvaccinated but challenged (A) and vaccinated and challenged (B, C, and D). The vaccinated groups were subdivided by vaccine type and inoculation route: SL subunit vaccine (hemagglutinin antigen 1 [HA1] + wild-type cholera toxin [wtCT], B); IM subunit vaccine (HA1 + aluminum hydroxide, C); and IM inactivated vaccine (+ aluminum hydroxide, D). The vaccines were administered twice at a 2-week interval. All pigs were challenged with pandemic influenza virus (A/swine/GCVP-KS01/2009 [H1N1]) and monitored for clinical signs, serology, viral shedding, and histopathology. After vaccination, hemagglutination inhibition titre was higher in group D (320) than in the other vaccinated groups (40–80) at the time of challenge. The mobility and feed intake were reduced in group C. Both viral shedding and histopathological lesions were reduced in groups B and D. Although this study has limitation due to the limited number of pigs (2 pigs per a group), the preliminary data in this study provided the protective potential of SL administration of bacteria-expressed pandemic H1N1 influenza vaccine in pigs. There should be additional animal studies about effective adjuvant system and vaccine types for the use of SL influenza vaccination.     

Influenza A virus coding regions exhibit host-specific global ordered RNA structure

Influenza A is a significant public health threat, partially because of its capacity to readily exchange gene segments between different host species to form novel pandemic strains. An understanding of the fundamental factors providing species barriers between different influenza hosts would facilitate identification of strains capable of leading to pandemic outbreaks and could also inform vaccine development. Here, we describe the difference in predicted RNA secondary structure stability that exists between avian, swine and human coding regions. The results predict that global ordered RNA structure exists in influenza A segments 1, 5, 7 and 8, and that ranges of free energies for secondary structure formation differ between host strains. The predicted free energy distributions for strains from avian, swine, and human species suggest criteria for segment reassortment and strains that might be ideal candidates for viral attenuation and vaccine development.     

Antibody Persistence in Adults Two Years after Vaccination with an H1N1 2009 Pandemic Influenza Virus-Like Particle Vaccine

The influenza virus is a human pathogen that causes epidemics every year, as well as potential pandemic outbreaks, as occurred in 2009. Vaccination has proven to be sufficient in the prevention and containment of viral spreading. In addition to the current egg-based vaccines, new and promising vaccine platforms, such as cell culture-derived vaccines that include virus-like particles (VLPs), have been developed. VLPs have been shown to be both safe and immunogenic against influenza infections. Although antibody persistence has been studied in traditional egg-based influenza vaccines, studies on antibody response durations induced by VLP influenza vaccines in humans are scarce. Here, we show that subjects vaccinated with an insect cell-derived VLP vaccine, in the midst of the 2009 H1N1 influenza pandemic outbreak in Mexico City, showed antibody persistence up to 24 months post-vaccination. Additionally, we found that subjects that reported being revaccinated with a subsequent inactivated influenza virus vaccine showed higher antibody titres to the pandemic influenza virus than those who were not revaccinated. These findings provide insights into the duration of the antibody responses elicited by an insect cell-derived pandemic influenza VLP vaccine and the possible effects of subsequent influenza vaccination on antibody persistence induced by this VLP vaccine in humans.     

Novel Viral Vectored Vaccines for the Prevention of Influenza

Influenza represents a substantial global healthcare burden, with annual epidemics resulting in 3–5 million cases of severe illness with a significant associated mortality. In addition, the risk of a virulent and lethal influenza pandemic has generated widespread and warranted concern. Currently licensed influenza vaccines are limited in their ability to induce efficacious and long-lasting herd immunity. In addition, and as evidenced by the H1N1 pandemic in 2009, there can be a significant delay between the emergence of a pandemic influenza and an effective, antibody-inducing vaccine. There is, therefore, a continued need for new, efficacious vaccines conferring cross-clade protection—obviating the need for biannual reformulation of seasonal influenza vaccines. Development of such a vaccine would yield enormous health benefits to society and also greatly reduce the associated global healthcare burden. There are a number of alternative influenza vaccine technologies being assessed both preclinically and clinically. In this review we discuss viral vectored vaccines, either recombinant live-attenuated or replication-deficient viruses, which are current lead candidates for inducing efficacious and long-lasting immunity toward influenza viruses. These alternate influenza vaccines offer real promise to deliver viable alternatives to currently deployed vaccines and more importantly may confer long-lasting and universal protection against influenza viral infection.     

Evolution trends of the 2009 pandemic influenza A (H1N1) viruses in different continents from March 2009 to April 2012

The World Health Organization (WHO) announced that the 2009 pandemic influenza A (H1N1) viruses, A/California/07/2009 (H1N1) — like virus, has gone into the post-pandemic period on August 10, 2010. People still have some concerns the virus would likely mutate and become a new pandemic virus in the future. Here, we use MUSCLE program and graphic mapping method to look into the evolutionary characteristics of the 6219 hemagglutinin and 4860 neuraminidase full-length sequences from March 2009 to April 2012. The graphic and statistical analyses showed that the novel pandemic isolates, A/California/07/2009 (H1N1) — like virus, experienced several different times. During the early-pandemic period (03/2009-08/2009), the viruses have spread globally in several clusters and deviated slightly from the recommended vaccine strain, A/California/07/2009. During the pandemic period (09/2009-08/2010), new clusters began to emerge from Asia and North America, and further deviated from the recommended vaccine strain. During the postpandemic period (09/2010-08/2011) and the recent period (09/2011-04/2012), the original cluster with the recommended vaccine isolate, A/California/07/2009, has nearly disappeared. The deviation degree between the new clusters and the vaccine isolate became larger and larger. However, the deviation degree and the deviation speed were low. The WHO did not choose a new vaccine isolate instead of the original vaccine isolate, A/California/07/2009. Even so, it is necessary to monitor continuously the 2009 pandemic influenza A (H1N1) viruses.     

Adaptation of high-growth influenza H5N1 vaccine virus in Vero cells: implications for pandemic preparedness

Current egg-based influenza vaccine production technology can't promptly meet the global demand during an influenza pandemic as shown in the 2009 H1N1 pandemic. Moreover, its manufacturing capacity would be vulnerable during pandemics caused by highly pathogenic avian influenza viruses. Therefore, vaccine production using mammalian cell technology is becoming attractive. Current influenza H5N1 vaccine strain (NIBRG-14), a reassortant virus between A/Vietnam/1194/2004 (H5N1) virus and egg-adapted high-growth A/PR/8/1934 virus, could grow efficiently in eggs and MDCK cells but not Vero cells which is the most popular cell line for manufacturing human vaccines. After serial passages and plaque purifications of the NIBRG-14 vaccine virus in Vero cells, one high-growth virus strain (Vero-15) was generated and can grow over 10(8) TCID(50)/ml. In conclusion, one high-growth H5N1 vaccine virus was generated in Vero cells, which can be used to manufacture influenza H5N1 vaccines and prepare reassortant vaccine viruses for other influenza A subtypes.