Helen Rees

Asymptomatic transmission, inequitable access to diagnostics, and rising antimicrobial resistance are major barriers to controlling the bacterial sexually transmitted infections (STIs) gonorrhea, chlamydia, and syphilis. Developing vaccines against these infections has therefore become a key STI research priority, requiring innovative research, expedited clinical development, and increased investment.

Background. Rapid COVID‐19 vaccine development occurred during the pandemic and vaccine‐related complications such as thrombosis with thrombocytopenia syndrome were discovered. Clinical trials and treating facilities included D‐dimer testing in COVID‐19 vaccine trials and COVID‐19 disease‐severity assessments, respectively. D‐dimer testing and result interpretation is complex and its use in isolation is controversial. Objectives. To evaluate D‐dimer levels in healthy adult participants regardless of HIV status, prior to and 2 weeks after receipt of fractional and full‐dose Ad26.COV2.S or Comirnaty booster COVID‐19 vaccination, after a full dose Ad26.COV2.S prime, stratified by booster vaccination arm, age and HIV status. Methods. BaSiS, a prospective open‐label trial, enrolled 289 healthy adults. Participants with controlled comorbidities, HIV infection with no immunological or virological exclusions, and no prior thrombosis enrolled at four sites in South Africa (SA). Participants previously received a single Ad26.COV2.S prime vaccination through the Sisonke phase IIIB open‐label implementation study or the COVID‐19 vaccine programme in SA. Participants were randomised 1:1:1:1 to receive one of four boosters: full‐dose Ad26.COV2.S, half‐dose Ad26.COV2.S, full‐dose Comirnaty or half‐dose Comirnaty. D‐dimer testing (INNOVANCE D‐dimer assay), as a coagulopathy marker, was conducted before the booster (baseline) and 2 weeks after the booster. The primary objectives previously reported included safety and immunogenicity of booster vaccination and fractional dosing with Ad26.COV2.S or Comirnaty in Ad26.COV2.S‐vaccinated participants. An exploratory objective evaluating clotting profiles, measured by D‐dimers, is reported here. Results. The median age among 285 evaluable participants included in this analysis was 42.2 (interquartile range (IQR): 35.5 ‐ 48.7) years; 82.5% (235/285) were female and 94.4% (269/285) were black African. Of the 40.4% (115/285) of people living with HIV, 79.1% (91/115) were well controlled on antiretroviral therapy. At baseline, 39.3% (112/285) of participants had elevated D‐dimer levels ‒ all asymptomatic. Females and obese participants were significantly more likely to have elevated baseline D‐dimer levels (adjusted odds ratio (aOR): 3.14, 95% confidence interval (CI): 1.32 ‐ 7.48 and aOR: 2.20, 95% CI: 1.22 ‐ 3.96, respectively). Of 276 participants with D‐dimer results available at 2 weeks after the booster, 109 (39.5%) had elevated D‐dimer levels. Those with elevated levels at baseline and female participants (aOR: 14.75, 95% CI: 7.64 ‐ 28.48 and aOR: 3.24, 95% CI: 1.14 ‐ 9.22, respectively) were significantly more likely to have elevated D‐dimer levels at 2 weeks. Conclusion. Elevated D‐dimer levels in asymptomatic, low‐risk adults were unexpectedly common and not associated with thromboembolism. This supports the rationale of including D‐dimer testing in conjunction with other coagulopathy markers, only if clinically indicated in both COVID‐19 vaccine clinical trials and the general population.

This Perspective article from Rebecca Grais and colleagues places a recently published study in PLOS Medicine in the context of the evolving landscape of vaccines and pregnancy.

We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4% showing evidence of previous SARS-CoV-2 infection. A total of 286 adults (with or without HIV) were enrolled >4 months after an Ad26.COV2.S prime and randomized 1:1:1:1 to receive either a full or half-dose booster of Ad26.COV2.S or BNT162b2 vaccine. B cell responses (binding, neutralization and antibody dependent cellular cytotoxicity-ADCC), and spike-specific T-cell responses were evaluated at baseline, 2, 12 and 24 weeks post-boost. Antibody and T-cell immunity targeting the Ad26 vector was also evaluated. No vaccine-associated serious adverse events were recorded. The full- and half-dose BNT162b2 boosted anti-SARS-CoV-2 binding antibody levels (3.9- and 4.5-fold, respectively) and neutralizing antibody levels (4.4- and 10-fold). Binding and neutralizing antibodies following half-dose Ad26.COV2.S were not significantly boosted. Full-dose Ad26.COV2.S did not boost binding antibodies but slightly enhanced neutralizing antibodies (2.1-fold). ADCC was marginally increased only after a full-dose BNT162b2. T-cell responses followed a similar pattern to neutralizing antibodies. Six months post-boost, antibody and T-cell responses had waned to baseline levels. While we detected strong anti-vector immunity, there was no correlation between anti-vector immunity in Ad26.COV2.S recipients and spike-specific neutralizing antibody or T-cell responses post-Ad26.COV2.S boosting. Overall, in the context of hybrid immunity, boosting with heterologous full- or half-dose BNT162b2 mRNA vaccine demonstrated superior immunogenicity 2 weeks post-vaccination compared to homologous Ad26.COV2.S, though rapid waning occurred by 12 weeks post-boost. Trial Registration: The study has been registered to the South African National Clinical Trial Registry (SANCTR): DOH-27-012022-7841. The approval letter from SANCTR has been provided in the up-loaded documents.

BaSiS ( B ooster A fter Si sonke S tudy) is a prospectively enrolled open-label trial in which healthy adults, with controlled co-morbidities and no prior thrombosis, who received a single Ad26.COV2.S prime vaccination primarily through the Sisonke phase IIIB open label implementation study in South Africa. An exploratory objective evaluated the clotting profiles of participants who were enrolled across 4 sites in South Africa and randomised 1:1:1:1 to receive one of full-dose Ad26.COV2.S, half-dose Ad26.COV2.S, full-dose Comirnaty or half-dose Comirnaty booster. D-dimer testing (INNOVANCE®D-Dimer Assay), as a coagulopathy marker, was conducted pre-booster (baseline) and 2 weeks post-booster. The median age among 285 participants was 42.2 years (IQR:35.5-48.7), 235/285 (82.5%) were female, 269/285 (94.4%) were Black African. Of the 40.4% (115/285) people living with HIV (PLHIV), 79.1% (91/115) were well-controlled on antiretroviral therapy. At baseline, 39.3% (112/285) had elevated d-dimers; all asymptomatic. Females and obese participants were significantly more likely to have elevated baseline d-dimers (OR=4.17; 95% CI:1.88 to 9.26 and OR=2.64; 95% CI:1.57 to 4.43, respectively). Of 169 with normal baseline d-dimers, 29 (17.2%) became elevated 2 weeks post-booster: median increase 0.23µg/ml (IQR:0.15-0.42); those receiving full-dose Comirnaty exhibited lower risk of d-dimer elevation post vaccination, compared to other booster vaccination arms (OR:0.26; 95% CI:0.07 to 0.98). PLHIV experienced significantly higher median increases compared to HIV uninfected participants (0.43 vs 0.17, p=0.004). Elevated d-dimers in asymptomatic, low-risk adults were unexpectedly common but were not associated with thromboembolism, supporting the rationale of using d-dimers only if clinically indicated. Trial Registration: South African Clinical Trails Register number DOH-27-012022-7841.

As of November 2023, 140 World Health Organization (WHO) member states had introduced human papillomavirus (HPV) vaccination in their routine immunization schedules. Despite a continuously increasing demand from countries across all income groups, supply constraints, COVID-19 pandemic disruptions, and other factors have slowed the pace of introduction, particularly in low-resource settings. Using a population-based forecasting methodology and leveraging the WHO’s yearly vaccine supply data collection, we updated global demand and supply projections for the HPV vaccine for the period of 2022–2031. The analysis aimed at clarifying the magnitude of the challenges to bringing in equitable access to HPV vaccines, which can hinder the achievement of the Global Strategy for the Elimination of Cervical Cancer. The results of this analysis show that the risk of HPV shortages has significantly decreased, and global supply is now, under normal circumstances, sufficient to meet global demand. In the long term, HPV supply will be more than sufficient to meet the Global Strategy’s goal of 90% of girls fully vaccinated with the HPV vaccine by the age of 15 years. Nonetheless, paying attention to the formulation of policies and carefully managing demand and supply will be required to ensure the long-term sustainability of the HPV vaccine program.

Background We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4% showing evidence of previous SARS-CoV-2 infection. Methods A total of 286 adults (with or without HIV) were enrolled >4 months after an Ad26.COV2.S prime and randomized 1:1:1:1 to receive either a full or half-dose booster of Ad26.COV2.S or BNT162b2 vaccine. B cell responses (binding, neutralization and antibody dependent cellular cytotoxicity-ADCC), and spike-specific T-cell responses were evaluated at baseline, 2, 12 and 24 weeks post-boost. Antibody and T-cell immunity targeting the Ad26 vector was also evaluated. Results No vaccine-associated serious adverse events were recorded. The full- and half-dose BNT162b2 boosted anti-SARS-CoV-2 binding antibody levels (3.9- and 4.5-fold, respectively) and neutralizing antibody levels (4.4- and 10-fold). Binding and neutralizing antibodies following half-dose Ad26.COV2.S were not significantly boosted. Full-dose Ad26.COV2.S did not boost binding antibodies but slightly enhanced neutralizing antibodies (2.1-fold). ADCC was marginally increased only after a full-dose BNT162b2. T-cell responses followed a similar pattern to neutralizing antibodies. Six months post-boost, antibody and T-cell responses had waned to baseline levels. While we detected strong anti-vector immunity, there was no correlation between anti-vector immunity in Ad26.COV2.S recipients and spike-specific neutralizing antibody or T-cell responses post-Ad26.COV2.S boosting. Conclusion In the context of hybrid immunity, boosting with heterologous full- or half-dose BNT162b2 mRNA vaccine demonstrated superior immunogenicity 2 weeks post-vaccination compared to homologous Ad26.COV2.S, though rapid waning occurred by 12 weeks post-boost. Trial Registration South African National Clinical Trial Registry (SANCR): DOH-27-012022-7841 Funding South African Medical Research Council (SAMRC) and South African Department of Health (SA DoH).

Background: As the COVID-19 pandemic spread in 2020, many governments across the globe put structures in place to access rapid independent scientific evidence. The South African Minister of Health established an advisory committee in March 2020 to provide high-level strategic advice. This technical guidance, developed as topic-specific ‘advisories’, was expected to be context-specific and based on the best available evidence, locally and internationally. The authors developing the advisories could draw on systems-wide, multidisciplinary experience. Approach: This chapter provides a reflective experience of the process of preparing advisories, the development of rapid evidence syntheses and their use in decision-making, the outputs and the lessons learned from that process, and the structural and operational changes over the course of the pandemic. As South Africa has moved out of the acute phase of the pandemic, the lessons learned must be embraced and best practices adopted to inform future pandemic preparedness. Advisories needed to use the best available evidence rather than wait for the best possible evidence. Some advisories were therefore revised multiple times, as new evidence emerged. Advisories were submitted to the Minister of Health for consideration prior to public release. However, in some cases, delays in such release led to confusion as to the scientific basis of policy decisions. The confidentiality of the committee debates also needed to be balanced against the need for engagement with the public. In order to promote accountability and build public trust, from March 2022 all advisories were published on a dedicated website within seven days of receipt by the Minister. The public were thus informed of the scientific basis of the advice, providing important context for subsequent executive decisions. Consistent feedback to the committee from decision-makers was also important, as their advice was only one of many inputs considered by a complex array of government bodies, across different departments. Conclusions: The world faces a significant risk of further pandemics and other public health emergencies and is engaged in high-level negotiations on strengthening global capacity to respond. Whether that involves a global pandemic accord, strengthened International Health Regulations, or a strengthened global approach to medical countermeasures, rapid, credible, independent and country-specific scientific advice will remain essential. The lessons learned during COVID-19 should not be lost. Submitted on behalf of the Ministerial Advisory Committee on COVID-19.

With increasing workplace and home pressures on all staff, nurses can support colleagues through open, honest discussions about the difficulties of coping and suicidal ideation In the BBC TV programme This is Going to Hurt, hospital staff plant a tree in memory of a colleague who has died by suicide. The events in the medical drama – which is based on the bestselling memoir of the same name by former NHS junior doctor Adam Kay – will resonate with many nurses, who understand the pressure and well-being risks of working in healthcare.

This Review initiates a wide-ranging discussion over 2023 by selecting and exploring core themes to be investigated more deeply in papers submitted to the Vaccines Special Issue on the “Future of Epidemic and Pandemic Vaccines to Serve Global Public Health Needs”. To tackle the SARS-CoV-2 pandemic, an acceleration of vaccine development across different technology platforms resulted in the emergency use authorization of multiple vaccines in less than a year. Despite this record speed, many limitations surfaced including unequal access to products and technologies, regulatory hurdles, restrictions on the flow of intellectual property needed to develop and manufacture vaccines, clinical trials challenges, development of vaccines that did not curtail or prevent transmission, unsustainable strategies for dealing with variants, and the distorted allocation of funding to favour dominant companies in affluent countries. Key to future epidemic and pandemic responses will be sustainable, global-public-health-driven vaccine development and manufacturing based on equitable access to platform technologies, decentralised and localised innovation, and multiple developers and manufacturers, especially in low- and middle-income countries (LMICs). There is talk of flexible, modular pandemic preparedness, of technology access pools based on non-exclusive global licensing agreements in exchange for fair compensation, of WHO-supported vaccine technology transfer hubs and spokes, and of the creation of vaccine prototypes ready for phase I/II trials, etc. However, all these concepts face extraordinary challenges shaped by current commercial incentives, the unwillingness of pharmaceutical companies and governments to share intellectual property and know-how, the precariousness of building capacity based solely on COVID-19 vaccines, the focus on large-scale manufacturing capacity rather than small-scale rapid-response innovation to stop outbreaks when and where they occur, and the inability of many resource-limited countries to afford next-generation vaccines for their national vaccine programmes. Once the current high subsidies are gone and interest has waned, sustaining vaccine innovation and manufacturing capability in interpandemic periods will require equitable access to vaccine innovation and manufacturing capabilities in all regions of the world based on many vaccines, not just “pandemic vaccines”. Public and philanthropic investments will need to leverage enforceable commitments to share vaccines and critical technology so that countries everywhere can establish and scale up vaccine development and manufacturing capability. This will only happen if we question all prior assumptions and learn the lessons offered by the current pandemic. We invite submissions to the special issue, which we hope will help guide the world towards a global vaccine research, development, and manufacturing ecosystem that better balances and integrates scientific, clinical trial, regulatory, and commercial interests and puts global public health needs first.