Vaccines and Public Trust: Containing COVID-19 in Cuba.

As 2021 drew to a close, Cuba struggled to contain the highly transmissible omicron variant of SARS-CoV-2, braced for a new wave of infections and kept a close eye on other variants of concern popping up around the world-a common experience to countries everywhere as we head into the second year of the pandemic. In Cuba, however, there is one marked difference making all the difference: by early January, 87% of the population was fully vaccinated using a three-dose schedule of vaccines developed and produced on the island.[1] This massive vaccination campaign is complemented by a rapid booster rollout-also using Cuban vaccines-that began in December 2021 and was ongoing as we finalized this issue. The island nation was able to achieve the third highest COVID-19 vaccination rate in the world[2] after decades of scientific investment, research, discovery and innovation; regulatory oversight and compliance; professional training; and increased production capacity. But a vaccine is only as effective as the health system charged with administering it-in a safe and timely manner, to as many people as possible. Here too, Cuba has decades of experience, including a national pediatric immunization program where 98% of children under 5 are immunized against 13 diseases,[3] an annual polio vaccination campaign (both launched in 1962 and uninterrupted since) and campaigns to contain epidemics such as H1N1. When the first COVID-19 cases were detected on the island in March 2020, Cuba harnessed this vaccine experience, making a hard tack towards developing its own vaccines. Two of the main protagonists in the country's biotechnology development, the Finlay Vaccine Institute (IFV) and the Genetic Engineering and Biotechnology Center (CIGB), both with several groundbreaking preventive and therapeutic vaccines in their portfolios, led the search for a vaccine. Today, Cuba has three vaccines authorized for emergency use-Soberana 02 and Soberana Plus developed by IFV, and Abdala, developed by CIGB. Schedules with these vaccines have demonstrated more than 90% efficacy in clinical trials,[4] and after regulatory approval for emergency use, became the backbone of Cuban COVID-19 vaccination efforts. A fourth vaccine, Mambisa (CIGB), administered nasally, and a fifth, Soberana 01 (IFV) are still in clinical trials. For this installment in MEDICC Review's series spotlighting leading women of Cuban science, we sat down with Dr Verena Muzio, Director of Clinical Research at CIGB. A pioneer of Cuba's biotechnology sector, she is an immunologist with a doctorate in biological sciences. Her professional trajectory began researching the genetically engineered hepatitis B surface antigen that led to the development of Cuba's recombinant hepatitis B vaccine in 1989. The same technological platform used in this vaccine was used to develop CIGB's Abdala vaccine against SARS-CoV-2-part of the reason Cuba was able to secure a vaccine so quickly. A phase 3 clinical trial determined a 92.28% efficacy rate for Abdala, with results to appear in forthcoming publications.

In Haiti, Cubans Among First Responders, Again: Luis Orlando Oliveros-Serrano MD Coordinator, Cuban Medical Team in Haiti.

Soaring summer temperatures, systematic urban and political violence, unreliable infrastructure-power outages, water shortages, sporadic transportation and interruption of other basic services-plus the illness, death and economic straits wrought by COVID-19, are what Haitians awake to every day. On the morning of August 14, 2021, they also woke to the earth in the throes of violent, lethal convulsions caused by a 7.2-magnitude earthquake, along the same fault line responsible for the devastating 2010 disaster and stronger still. As if this weren't enough, Tropical Storm Grace was bearing down on the nation, about to dump biblical amounts of rain on the heels of Tropical Storm Fred. When the Haitian President was assassinated on July 7, Haiti still had not received a single dose of any COVID-19 vaccine-indeed, it was the last country in the Americas to receive vaccines. Later that month, 500,000 doses arrived in the country, donated by the United States via COVAX, the WHO-led initiative to assure at least some vaccines reached low- and middle-income countries. In Haiti, getting those vaccines into the arms of the population is beset by cold chain, distribution and bureaucratic problems, and compounded by widespread vaccine hesitancy; when the earthquake struck, only 14,074 of those doses had been administered.[1,2] Suddenly there was a new, more urgent tragedy, the earthquake leaving thousands of dead, injured and displaced-perhaps hundreds of thousands once the real tally emerges. As in the 2010 quake, the doctors, nurses and technicians comprising Cuba's medical team in Haiti-a commitment Cuba has maintained with its Caribbean neighbor since 1998-were among the first responders. The 2010 relief effort included an additional 1500 health professionals and specialists from Cuba's Henry Reeve Emergency Medical Contingent. Just 24 hours after the August 14th quake, MEDICC Review spoke by phone with Dr Luis Orlando Oliveros-Serrano in Port-au-Prince, where he coordinates Cuba's medical team in Haiti. His disaster response experience had already taken him to Haiti twice before and to Pakistan, Bolivia and beyond.

COVID-19 Requires Innovation, Regulation and Rigor: Amaylid Arteaga-García MD MS Director, National Clinical Trials Coordinating Center (CENCEC).

The effects and implications of COVID-19 are global, comprehensive and long-term. The pandemic has exposed inequities, the fragility of economic and political systems, and in many cases, skewed priorities. Population health, not to mention planetary health, is suffering as a result. Nevertheless, the global health crisis in which we are embroiled has provided opportunities for effective collaboration, scientific innovation and real dialog around health and equity. Dr Amaylid Arteaga-García, director of Cuba's National Clinical Trials Coordinating Center (CENCEC), emphasized these opportunities when discussing Cuba's clinical trials in times of COVID-19. Founded in 1991 in response to the groundbreaking research emerging from the country's biopharmaceutical sector-including the first safe, effective vaccine against serogroup B meningococcal disease, VA-MENGOC-BC in 1989 and a recombinant vaccine against hepatitis B, Heberbiovac in 1990-CENCEC now coordinates some 100 clinical trials annually, many of them multi-site trials involving thousands of volunteers. Little did Dr Arteaga García know what problems lurked when she became CENCEC director in 2019. In February 2020, Cuba implemented its National COVID-19 Prevention & Control Plan. This included a scientific Innovation Committee tasked with evaluating promising projects, products and research that might be used in the health system to control and treat COVID-19. This approach taps into two of Cuba's strengths: biotechnology and primary health care. Given the volume and complexity of COVID-19 clinical trials, Dr Arteaga.

Cuba's National Regulatory Authority & COVID-19: Olga Lidia Jacobo-Casanueva MS Director, Center for State Control of Medicines and Medical Devices (CECMED).

At the time of this writing, more than 10 million Cubans (nearly 90% of the country's population), had received at least their first dose of Soberana 02 or Abdala, two of five vaccine candidates for SARS-CoV-2 developed and produced on the island. Late-phase clinical trial data revealed that Abdala is 92.28% effective after the full, three-dose cycle and Soberana 02 is 91.2% effective after two doses, when followed by a booster of Soberana Plus.[1] Cuban health authorities have committed to vaccinating the entire population, including children aged 3-18 years old, using these vaccines by the end of 2021. The first pre-clinical, peer-reviewed data are available,[2] with clinical trial results already submitted to various international journals. Building on decades of biotechnology know-how developing, producing and administering 11 preventive vaccines for childhood diseases-used in the nation's universal health system and also marketed elsewhere-Cuba is the first, and to date only, country in Latin America and the Caribbean to develop its own vaccine candidates for COVID-19 (Soberana 01; Soberana 02; Soberana Plus; Abdala and Mambisa; see Box on following page). In a strategy designed to ensure comprehensive and importantly, independent solutions to the global health crisis, research institutes and manufacturing facilities coordinated by BioCubaFarma-the country's biopharmaceutical conglomerate-have also developed COVID-19 treatments and essential medical equipment. To gain a better understanding of the regulatory process involved, MEDICC Review turned to Olga Lidia Jacobo-Casanueva, Director of the Center for State Control of Medicines and Medical Devices (CECMED), Cuba's national regulatory authority (NRA). A clinical microbiologist, Jacobo-Casanueva served as interim director throughout 2020 before becoming director in January 2021. She has spent nearly her entire career at CECMED, working her way up the ranks in a unique trajectory: from her first position in 1992 in the Center's microbiology laboratories, she has since worked in all but one of the six areas required by WHO to qualify as a National Regulatory Authority of Reference (NRAr; CECMED was certified as a Level 4 NRAr in 2011, a qualification it maintains). In short, Jacobo-Casanueva is a regulatory polymath, with hands-on experience in nearly every facet of regulation. She is also an adjunct researcher in the Faculty of Biology at the University of Havana. Cuba's decision to confront the pandemic autonomously by developing preventive vaccines to control COVID-19 is deliberate and fraught with challenges. With dozens of ongoing clinical trials, coupled with the declining epidemiological and economic situation in Cuba-exacerbated by tightened US sanctions affecting all facets of COVID-19 prevention and response-we appreciate the time Jacobo-Casanueva took from her schedule to parse the complex regulatory mechanisms required to introduce Cuban and imported products into the national health system. Editor's note: Just days after this interview was conducted in Havana, CECMED granted Emergency Use Authorization for Abdala, one of five Cuban COVID-19 vaccine candidates undergoing clinical trials since 2020.

Science as a Social Good: Iramis Alonso-Porro Director, Juventud Técnica.

Science journalism was little known in Cuba when Iramis Alonso wrote her the-sis on the specialized fi eld in 1990. That year, journalism degree from the Uni-versity of Havana in hand, she set off to Cuba's eastern countryside to complete two years of social service reporting for local, regional and national print media. Living in the mountains of Holguín, a typical day for the cub reporter took her to caves, forests and fi elds for stories on the intersection of science, culture and the environment. Alonso credits this formative experience with igniting her passion for investigative and sci-ence journalism, setting her on a unique career path as a journalist and editor specializing in the sciences writ large: climate change, astronomy, mathemat-ics and other hard sciences, engineer-ing, information technologies and social sciences, among others.

Monoclonal Antibodies vs COVID-19: Eduardo Ojito-Magaz MS General Director, Molecular Immunology Center.

Cuba has five COVID-19 vaccines in clinical trials and is on track to receive emergency use authorization from the country's regulatory agency to begin mass vaccination with two of those candidates: Abdala and SOBERANA 02. Results from phase 1 and 2 trials of these vaccines, the first developed and produced in Latin America, have been encouraging, both in terms of safety and immunogenicity. The ongoing phase 3 trials will continue to look at safety, together with efficacy; parallel intervention studies involving over a million people in Havana will begin generating data on effectiveness. Coordination between Cuba's biotechnology sector and its public health system-particularly throughout the different levels of primary care-to control and treat COVID-19 is a cornerstone of the Cuban strategy and one that could serve as a blueprint for future pandemics. Another Cuban product, itolizumab, is showing positive results mitigating cytokine release syndrome (CRS) in COVID-19 patients with moderate-to-severe acute respiratory distress syndrome (ARDS). Developed in collaboration with Biocon (India), itolizumab is administered under an expanded access program to treat vulnerable populations in Cuba. Marshaling complementary capacities of dozens of institutions belonging to BioCubaFarma-the country's biotech conglomerate-and developing therapies, vaccines and medical technologies together, is another cornerstone of Cuba's strategy to combat COVID-19 and improve population health. The Molecular Immunology Center (CIM) is a key player in this strategy. Founded in 1992, CIM is a powerhouse in monoclonal antibody research and production, with 6 registered products and 22 in the pipeline. Known for several novel therapeutic cancer treatments, CIM has over two decades' experience producing complex recombinant proteins in mammalian cells on an industrial scale. Once Cuba's Innovation Committee (convened in January 2020 as part of the National COVID-19 Prevention & Control Plan) determined Cuban researchers would pursue protein subunit vaccine candidates, they turned to CIM to produce the required receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, among other responsibilities. CIM's General Director, Dr Eduardo Ojito-Magaz, is a chemical engineer and holds a master's degree in biotechnology. He spoke with MEDICC Review just days before 1.7 million Havana residents began participating in the country's largest intervention study with the COVID-19 vaccines his center helped make possible.

"Cuba's Medical Team in the European Epicenter of COVID-19: Carlos R. Pérez-Díaz MD MS PhD Director, Joaquín Albarrán Provincial Clinical-Surgical Hospital, Havana Henry Reeve Medical Contingent Leader, Lombardy, Italy".

On March 23, 2020, Cuba's Henry Reeve Emergency Medical Contingent began treating COVID-19 patients at Maggiore Hospital in Crema, Lombardy. Within days, the 52-member contingent comprised of 36 doctors and 15 nurses (plus 1 logistics specialist), together with Italian colleagues, were receiving patients in an adjacent fi eld hospital established and equipped for this purpose. At the time, Lombardy was the epicenter of COVID-19 transmission in Europe. Many of the Cubans in Lombardy were Contingent veterans, having served in postdisaster and epidemic scenarios in Chile, Pakistan, Haiti and elsewhere since the founding of the emergency medical team in 2005. Importantly, some had worked fi ghting the 2014 Ebola epidemic in West Africa. Even so, providing medical care during COVID-19 is a unique challenge, the likes of which had never before been seen by the Cuban team. Dr Carlos R. Pérez-Díaz, one of the Contingent's founding members, headed the team during its 60-day rotation in Lombardy, drawing on a wide array of professional experience. From 2006 to 2009, Dr Pérez-Díaz led the Cuban team posted at the Peltier Hospital in Djibouti, where he worked in the infectious disease department; in 2008, this team helped control a cholera outbreak that had spread to three countries. Following the 2010 earthquake in Chile, Dr Pérez-Díaz headed the team of Henry Reeve volunteers that provided free health services for 10 months in a tent hospital established to treat victims; he returned to Chile in 2015, again as head of the Henry Reeve Contingent, after severe fl ooding struck the Atacama region.

SOBERANA, Cuba's COVID-19 Vaccine Candidates: Dagmar García-Rivera PhD.

On August 13, 2020, Cuba's national regulatory agency, the Center for Quality Control of Medicines, Equipment and Medical Devices (CECMED), authorized clinical trials for SOBERANA 01-Cuba's fi rst vaccine candidate and the fi rst from Latin America and the Caribbean. On August 24, parallel Phase I/II double blind, randomized, controlled clinical trials were launched at clinical sites in Havana to evaluate the vaccine's safety and immunogenicity. Analysis of results and development of different formulations are currently under way and Phase III clinical trials are planned for early 2021. At the time of writing, a second vaccine candidate, SOBERANA 02, was in late-stage development and preparing to begin separate trials this fall.

SOBERANA, Cuba's COVID-19 Vaccine Candidates: Dagmar García-Rivera PhD.

On August 13, 2020, Cuba's national regulatory agency, the Center for Quality Control of Medicines, Equipment and Medical Devices (CECMED), authorized clinical trials for SOBERANA 01-Cuba's fi rst vaccine candidate and the fi rst from Latin America and the Caribbean. On August 24, parallel Phase I/II double blind, randomized, controlled clinical trials were launched at clinical sites in Havana to evaluate the vaccine's safety and immunogenicity. Analysis of results and development of different formulations are currently under way and Phase III clinical trials are planned for early 2021. At the time of writing, a second vaccine candidate, SOBERANA 02, was in late-stage development and preparing to begin separate trials this fall.

Early Action, Applied Research & Collaboration to Combat COVID-19: María Guadalupe Guzmán MD PhD DSc.

Virologist Dr María Guadalupe Guzmán is recognized as a global leader in dengue research and heads the Pedro Kourí Tropical Medicine Institute's work as a WHO/PAHO Collaborating Center for the Study of Dengue and Its Vector. The Institute (IPK) was founded in 1937 and is now Cuba's national reference center for the diagnosis, treatment, control and prevention of communicable diseases. Dr Guzmán is also president of the Cuban Society of Microbiology and Parasitology and directs IPK's Scientifi c Council, which is responsible for setting the Institute's research priorities. A recent h-index analysis found that Dr Guzmán is among the most widelypublished and cited Cuban researchers.

Early Action, Applied Research & Collaboration to Combat COVID-19: María Guadalupe Guzmán MD PhD DSc.

Virologist Dr María Guadalupe Guzmán is recognized as a global leader in dengue research and heads the Pedro Kourí Tropical Medicine Institute's work as a WHO/PAHO Collaborating Center for the Study of Dengue and Its Vector. The Institute (IPK) was founded in 1937 and is now Cuba's national reference center for the diagnosis, treatment, control and prevention of communicable diseases. Dr Guzmán is also president of the Cuban Society of Microbiology and Parasitology and directs IPK's Scientifi c Council, which is responsible for setting the Institute's research priorities. A recent h-index analysis found that Dr Guzmán is among the most widelypublished and cited Cuban researchers.

COVID-19 Case Detection: Cuba's Active Screening Approach.

Meningitis, neuropathy, HIV, dengue-since the 1960s, Cuba has faced its share of epidemics. More recently, Cuban health pro-fessionals tackled domestic outbreaks of H1N1 (2009) and Zika (2016), and worked alongside colleagues from around the world to stem Ebola in West Africa; all three were categorized by WHO as public health emergencies of international concern. In December 2019, China reported its fi rst cluster of pneumo-nia cases, later identifi ed as the novel coronavirus disease COVID-19. In January 2020, Cuban authorities convened a multi-sector working group coordinated by the Ministry of Pub-lic Health (MINSAP) and Civil Defense to tailor its national epi-demic control plan to confront the rapidly-spreading disease. The plan features a national reporting system and database, with standard protocols including early case detection, contact tracing and regularly-scheduled public health messaging. In late January, no fewer than six ministries, plus the National Sports and Recreation Institute, Customs, Immigration and national media outlets, came together to adapt domestic proto-cols and design multi-phase control and response mechanisms to combat the SARS-CoV-2 virus.

Global Collaboration in Times of COVID-19: Cuba's Emergency Medical Contingent.

The days are long and arduous, with end-less patients to attend, often in a foreign language, always on foreign shores. Far from family and the familiar. Sleep is fi tful at best for health profession-als serving in emergency situations-when sickness obeys no clock and patients' pain haunts even the quiet moments. The crisis scenario varies: post-earthquake, hurricane or tsunami; amid a cholera or Ebola epidemic. The countries vary: Haiti, Pakistan, Guatemala, Mozambique, Sierra Leone. What does not vary is the answer to the calls for help and Cuban professionals' commitment to care for the most vulner-able. These aren't armchair musings or a political pat on the back: they are my own conclusions after living for weeks in close-quarter tents with Cuban doctors, nurses and biomedical engineers in post-earth-quake Pakistan and Haiti, and witnessing their work.