How to accelerate the supply of vaccines to all populations worldwide? Part II: Initial industry lessons learned and detailed technical reflections leveraging the COVID-19 situation.

Vaccine discovery and vaccination against preventable diseases are one of most important achievements of the human race. While medical, scientific & technological advancements have kept in pace and found their way into treatment options for a vast majority of diseases, vaccines as a prevention tool in the public health realm are found languishing in the gap between such innovations and their easy availability/accessibility to vulnerable populations. This paradox has been best highlighted during the unprecedented crisis of the COVID-19 pandemic. As part of a two series publication on the vaccine industry's view on how to accelerate the availability of vaccines worldwide, this paper offers a deep dive into detailed proposals to enable this objective. These first-of-its-kind technical proposals gleaned from challenges and learnings from the COVID-19 pandemic are applicable to vaccines that are already on the market for routine pathogens as well as for production of new(er) vaccines for emerging pathogens with a public health threat potential. The technical proposals offer feasible and sustainable solutions in pivotal areas such as process validation, comparability, stability, post-approval changes, release testing, packaging, genetically modified organisms and variants, which are linked to manufacturing and quality control of vaccines. Ultimately these proposals aim to ease high regulatory complexity and heterogeneity surrounding the manufacturing & distribution of vaccines, by advocating the use of (1) Science and Risk based approaches, (2) global regulatory harmonization, (3) use of reliance, work-sharing, and recognition processes and (4) digitalization. Capitalizing & collaborating on such new-world advancements into the science of vaccines will eventually benefit the world by turning vaccines into vaccination, ensuring the health of everyone.

Regulatory Harmonization and Streamlining of Clinical Trial Applications globally should lead to faster clinical development and earlier access to life-saving vaccines.

Vaccines continue to play a central role in our ability to prevent disease, save lives, and improve health. The scientific community, including our own researchers, are driven by a shared purpose to improve vaccine technologies and bring the benefits of immunization to everyone, regardless of where they live - as soon as possible, especially when the medical need is considerable. Vaccine developers and manufacturers (sometimes referred to as "study sponsors" or "applicants") are exploring technological advancements to translate breakthrough discoveries into novel vaccines which have the potential to provide protection from life-threatening and debilitating infectious diseases. Developing new vaccines is a lengthy process regulated by guidance provided by independent organizations, National Regulatory Authorities (NRAs) and the World Health Organization. As most infectious diseases can span a considerable area of the world, clinical trials are often conducted across different countries and regions. Regulatory requirements for clinical trials (both Chemistry Manufacturing & Controls - CMC, nonclinical and clinical) vary significantly between the different countries and regions adding to the complexity of vaccine development and leading to significant delays in the development of novel vaccines and ultimately equitable access for populations to these innovations. Without progress in terms of regulatory convergence and harmonization the benefits from these scientific advancements will not be fully realized. There is an urgent need by global bodies such as WHO to partner with and the NRAs to establish and implement.

Alignment in post-approval changes (PAC) guidelines in emerging countries may increase timely access to vaccines: An illustrative assessment by manufacturers.

A comparison of the regulations and guidelines from 33 countries, across different regions, on the requirements and procedures for the management of chemical, manufacturing and control (CMC) changes for vaccines, also known as post- approval changes (PACs), reveals significant variability and lack of predictability of timelines for regulatory review and approval. These shortcomings imply that multiple data packages have to be prepared for submission to different authorities, generating a complex regulatory environment. Moreover, the timelines for approval by individual national regulatory authorities are variable, which results in manufacturers keeping various stocks of vaccines produced in accordance with the various approved specifications and procedures, in the different countries. This can seriously affect timely availability of vaccine in those countries. The World Health Organization (WHO) guidelines on procedures and data requirements for changes to approved vaccines provide a consensual framework for alignment, but are still underused. Reliance on both the review and approval by the regulatory authority in the country of manufacturing, or on the review performed by other national regulatory authorities, recognized by WHO as stringent, or on WHO prequalification dossier, offer alternative ways forward. These and other options to improve the management of post-approval changes during the product lifecycle of vaccines are discussed in this report, and aimed at improving guidelines alignment and regulatory convergence to advance immunization equity and coverage.

Epidemiology of travelers' diarrhea: details of a global survey.

BACKGROUND: Recent epidemiologic data on travelers' diarrhea (TD) are essential for the evaluation of conventional and future prophylactic and therapeutic measures. METHODS: To determine the epidemiology, including risk factors, impact and quality-of-life evaluation of TD, a cross-sectional survey was conducted over 12 months at the airports of Mombasa (Kenya), Goa (India), Montego Bay (Jamaica) and Fortaleza (Brazil) by distributing questionnaires to visitors just prior to their flying home. The study period was March 1996 to July 1998. RESULTS: Overall, 73,630 short-term visitors completed a questionnaire. The total diarrhea attack rate varied between a high of 54.6% in Mombasa and a low of 13.6% in Fortaleza, but only between 31.5% and 5.4% of all travelers had classic TD. The 14-day incidence rates varied between 19.5% and 65.7%. Few travelers meticulously avoided potentially dangerous food items, although in India and Kenya most travelers avoided those considered most dangerous. Risk factors were stays exceeding 1 week, age between 15 and 30 years, and residence in the UK. The impact, measured as incapacity or quality-of-life scores, was very considerable. CONCLUSIONS: TD continues to affect vacationers and business travelers as frequently as it did some 20 years ago. Compliance with recommendations to reduce exposure to pathogens by avoiding dangerous food items is poor among travelers from all countries. Implementation of food safety education programs may be difficult to achieve.

Immune response of HLA DQ2 positive subjects, vaccinated with HBsAg/AS04, a hepatitis B vaccine with a novel adjuvant.

About 5-10% of the general adult population respond inadequately to hepatitis B vaccination. The histocompatibility leucocyte antigen (HLA) DQ2, DR3 and DR7 phenotypes have been linked with non-responsiveness to hepatitis B vaccination. A first part of our study determined the prevalence of the HLA DQ2 allele in a healthy population, aged 15-50 years. We found 35% of our study population (n=1008) positive for the HLA DQ2 allele. Positive subjects for HLA DQ2 were subsequently invited to participate in a trial and were to be given either the HBsAg/AS04 hepatitis B vaccine or a licensed hepatitis B vaccine (Engerix-B).(1) Both contained 20 microg of recombinant HBsAg. The HBsAg/AS04 vaccine was administered on a 0 and 6 months schedule whilst the comparator vaccine was given according to the standard 0, 1 and 6 months schedule. The experimental vaccine was formulated on a novel adjuvant containing 3' deacylated monophosphoryl lipid A (3D-MPL) and alum. A total of 230 subjects were enrolled into the vaccination study. At month 7, 99% of the subjects had a protective titre (>or=10mIU/ml) with a geometric mean titre (GMT) of 6613mIU/ml in the group receiving HBsAg/AS04 versus 97% seroprotected with a GMT of 2315mIU/ml in the other group. Both vaccines, with their respective schedule, give very high seroprotection rates (>96%). Our data suggest that HLA DQ2 positivity is not a good marker for non- or poor-responsiveness. The HBsAg/AS04 vaccine was more reactogenic mainly because of an increased local reactogenicity. Both vaccines, especially HBsAg/AS04, are highly immunogenic and well tolerated by the study subjects.

Combined vaccination against hepatitis A, hepatitis B, and typhoid fever: safety, reactogenicity, and immunogenicity.

BACKGROUND: The etiological agents of hepatitis A, hepatitis B, and typhoid fever share similar patterns of global distribution, and cause significant disease burden in travelers to endemic countries. Combined vaccination against all three diseases, based on currently available vaccines, would promote compliance and convenience for travelers. This clinical study evaluated the feasibility of extemporaneously syringe-mixed hepatitis A and B vaccine (Twinrix) and a Vi polysaccharide vaccine (Typherix) in healthy adults, and compared this to concomitant administration of the vaccines in separate arms. METHODS: The mixed dose of vaccine contained at least 720 enzyme-linked immunosorbent assay (ELISA) units of the inactivated hepatitis A antigen, 20 microg of the recombinant hepatitis B antigen and 25 microg of the Vi polysaccharide typhoid antigen in 1.5 mL. The study was conducted in 200 healthy 18- to 45-year-old volunteers. RESULTS: Equivalence between the vaccines mixed before administration and the concomitantly administered vaccines was shown in terms of seroconversion and seroprotection. With the exception of local injection site soreness, which was higher in the mixed administration group, the reactogencity was similar for both groups. In both vaccination groups more than 95% of the subjects were anti-hepatitis A virus and anti-Vi seropositive 1 month after the first vaccination. With regard to hepatitis B, a strong response was achieved in both groups, with more than two-thirds of the subjects protected 2 months after the start of the immunization course. CONCLUSION: These results support the feasibility of extemporaneously syringe-mixed combined hepatitis A and B vaccine with a Vi polysaccharide typhoid vaccine, administered in healthy adults.

Traveler's diarrhea: epidemiology and impact on visitors to Fortaleza, Brazil.

OBJECTIVE: To assess the epidemiology and impact of traveler's diarrhea (TD) among visitors to the city of Fortaleza, Ceará, Brazil, as part of a global study on TD carried out in four countries. METHODS: Within a cross-sectional survey, questionnaires were completed by departing travelers at the Fortaleza airport between March 1997 and February 1998. The questions inquired about demographics, duration of stay, reason for their visit, pretravel health advice they had received, risky food and beverage consumption while in Fortaleza, and quality of life during the visit to Fortaleza in relation to having or not having contracted TD. RESULTS: A total of 12,499 questionnaires were analyzed. The most common reason that the visitors gave for their travel to Fortaleza was a holiday (60.3%). The total diarrhea attack rate was 13.4%. Younger people (< 36 years) had significantly higher TD attack rates than did older persons. Using a logistic regression model, we investigated the visitors' risk factors, including age, gender, length of stay, and trip's purpose. According to that analysis, characteristics that are slightly predictive of TD are gender, length of stay, and visiting as a tourist rather than for some other purpose. Characteristics that protect against contracting TD include being older and traveling for business rather than for some other reason. Of those who were incapacitated by TD, the mean duration of the impairment was 42 hours. CONCLUSIONS: TD affected the travel plans and activities of many of the visitors to Fortaleza. Further, although aware of the health risks, the majority of those travelers did not avoid all potentially contaminated food or beverage items. Given this pattern of behavior, future efforts to combat TD may have to depend on such other alternative strategies as new vaccines.

Magnitude and quality of antibody response to a combination hepatitis A and hepatitis B vaccine.

Interference between antibodies generated by a combination hepatitis A and B vaccine was investigated by evaluating the quantity and quality of anti-hepatitis A virus (HAV) and anti-hepatitis B surface antigen (HBs) antibodies generated by Twinrix (Hepatitis A Inactivated and Hepatitis B (Recombinant) Vaccine). The magnitude of the immune response was determined by a retrospective analysis of eight clinical trials, completed during stepwise development of Twinrix. The functionality of anti-HAV was evaluated by comparison of routine ELISA results with neutralization assays and was further characterized by defining the epitope-specificity of binding. Functionality of the anti-HBs response was not tested because a validated assay was not developed at the time this study was conducted. Results of all analyses demonstrated that the combination vaccine induced high antibody titers against hepatitis A and B and a functional anti-HAV response, with no evidence of immune interference to either viral antigen.