safety

COVID-19 vaccines in patients with cancer: immunogenicity, efficacy and safety

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Abstract

Patients with cancer have a higher risk of severe coronavirus disease (COVID-19) and associated mortality than the general population. Owing to this increased risk, patients with cancer have been prioritized for COVID-19 vaccination globally, for both primary and booster vaccinations. However, given that these patients were not included in the pivotal clinical trials, considerable uncertainty remains regarding vaccine efficacy, and the extent of humoral and cellular immune responses in these patients, as well as the risks of vaccine-related adverse events. In this Review, we summarize the current knowledge generated in studies conducted since COVID-19 vaccines first became available. We also highlight critical points that might affect vaccine efficacy in patients with cancer in the future.

Key points

  • Vaccination against COVID-19 administered according to current prime–boost concepts is both safe and clinically effective in patients with cancer.
  • To date, no reliable correlate of protection that allows the definite deduction of clinical efficacy from immune responses has been established, either in patients with cancer or in the general population.
  • Patient-associated factors such as advanced age, haematological malignancy and/or treatment-associated factors such as B cell depletion might all lead to less proficient immune responses following vaccination.
  • Future research will determine the necessity of further booster regimens as well as therapeutic options for those who do not benefit from active COVID-19 vaccination.

Conclusions

The development of COVID-19 vaccines has been a massive global effort, leading to a marked reduction in the risk of severe COVID-19 and death. Encouragingly, the available vaccines are safe and effective in patients with cancer, although lower VE has been observed than in those without cancer. A high proportion of patients with solid tumours will develop both humoral and T cell responses following vaccination, although cancer therapies such as chemotherapy can suppress these responses. Patients with haematological malignancies are more vulnerable to breakthrough infections given the reduced VE and often limited immune responses in many of these patients, especially those with B cell malignancies receiving B cell-depleting therapies. Booster vaccines can result in seroconversion in those who were previously seronegative following two vaccine doses. This observation indicates that regular booster vaccines might be effective for immunocompromised patients with cancer. Additionally, high vaccination rates in the community, especially among the families of vulnerable patients and in clinical care settings, will help protect those with impaired vaccine responses.

Eloctate and Alprolix Show Long-Term Effectiveness for Hemophilia in Extension Studies

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Eloctate and Alprolix Show Long-Term Effectiveness for Hemophilia in Extension Studies

Treatment of severe hemophilia A with Eloctate and hemophilia B with Alprolix was safe and improved the patients’ annualized bleed rates (ABRs) over four years, according to the results of two extension studies announced by Bioverativ and Sobi.

The two open-label extension studies — ASPIRE (NCT01454739), and B-YOND (NCT01425723) — evaluated long-term preventive treatment with the two therapies in previously treated adult, adolescent, and pediatric patients. The lower ABRs included joint bleeds and were observed across all patient populations and at extended dosing intervals.

According to the team, the findings support the idea that preventive treatment with Eloctate – marketed as Elocta in Europe and the Middle East – and Alprolix is effective in the management of all types of joint bleeds.

Safety data was consistent with the pivotal Phase 3 trials. No patient showed development of inhibitors, a serious complication for people with hemophilia treated with clotting factors.

The results were presented at the recent 60th Annual Meeting of the American Society of Hematology in San Diego.

“These data add to a significant body of evidence showing that Eloctate and Alprolix provide protection from all types of hemophilia-related bleeds with individualized and flexible dosing regimens across all study populations,” Tim Harris, PhD, executive vice president, research and development at Bioverativ, said in a press release. “We remain focused on and committed to providing complete protection for people with hemophilia.”

Both Eloctate and Alprolix are engineered extended half-life blood clotting factors. Half-life refers to the time the body takes to halve the amount of a compound. The two therapies had previously shown efficacy in all treatment situations, such as acute, surgical, and emergency situations.

The therapies are marketed by either Bioverativ, a Sanofi company, or Sweden-based Sobi, depending on the region of the world.

ASPIRE included participants who had completed the pivotal, Phase 3 A-LONG (NCT01181128) or Kids A-LONG (NCT01458106) studies. It enrolled 211 male patients, 150 from A-LONG and 61 from Kids A-LONG. The primary objective was the development of inhibitors. Secondary goals included the annualized number of bleeding episodes, Eloctate’s exposure days, and the participants’ assessment of treatment response.

Results showed that treatment with Eloctate enabled low overall median ABRs throughout the study, especially in patients on individualized dosing. Some of these patients (across all age groups) demonstrated zero spontaneous joint bleeds. In addition, median joint ABRs of less than 0.66 were shown in the different groups.

Adults and adolescents experienced an improvement in joint health, as shown by a mean modified hemophilia joint health (mHJHS) score of -2.5 (a negative value means improvement) compared with initial values in A-LONG. The mHJHS score grades joints by specific domains that include swelling, muscle atrophy (shrinkage), alignment, range of motion, joint pain, strength, and global gait. The team cautioned that further studies will be needed to confirm these results.

More than 92% of participants either lengthened or had no difference in dosing intervals during the course of ASPIRE. Overall, the low ABRs and the improved joint health illustrate a clinical benefit that goes beyond bleed prevention, according to the scientists.

B-YOND included patients who completed the Phase 3 B-LONG (NCT01027364) or Kids B-Long (NCT01440946) trials. It enrolled 116 previously treated males — 93 from B-LONG, and 27 from Kids B-LONG. Results from these studies supported an update to Alprolix’s label to include pediatric data.

Similar to ASPIRE, the primary outcome was development of inhibitors. Secondary goals were the annualized number of bleeding episodes, including spontaneous joint bleeding rates, Alprolix’s exposure days and consumption, and the participants’ assessment of response to treatment.

As in ASPIRE, ABRs were low during the study in all ages, particularly in joint and spontaneous joint bleeds. Median joint and spontaneous joint ABRs were lower than 1.58 and 0.38, respectively, in adults and adolescents on preventive treatment with Alprolix. These values were under 0.85 and zero in participants younger than 12.

Additionally, 85% of adults and 93% of pediatric patients either lengthened or had no change in dosing intervals during B-YOND. Overall, treatment with Alprolix provided flexible dosing associated with consistently low bleeding rates with extended interval dosing of up to 14 days.

According to the researchers, B-YOND reflects the real-life use of Alprolix, with dosing changes based on patient preferences and their clinical profile and needs.

Hepatitis E Vaccine Efficacious and Safe

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In a large phase III trial conducted among adults in China, three doses of the vaccine had 100% efficacy at 1 year.

Hepatitis E virus (HEV) is widespread and continues to cause large outbreaks in developing countries. One recombinant vaccine was shown to be safe and immunogenic in men in Nepal, where only one of the four HEV genotypes had been isolated (JW Infect Dis Feb 28 2007). Could a vaccine derived from HEV genotype 1 protect against other genotypes in a general adult population? To find out, investigators (2 of whom were employees of the vaccine maker) conducted a double-blind, phase III trial of another candidate vaccine in a region of China where genotypes 1 and 4 circulate.

A total of 112,604 healthy adults (56% women) aged 16 to 65 were randomized to receive three doses of recombinant hepatitis E antigen (vaccine group) or hepatitis B vaccine (placebo group), administered at 0, 1, and 6 months. Cases of suspected hepatitis E were identified through enhanced surveillance and confirmed by presence of acute illness lasting ≥3 days, elevated serum alanine aminotransferase concentrations (≥2.5 times the upper limit of normal), and positive test results (HEV IgM and RNA, ≥4-fold increase in HEV IgG, or both).

Overall, 23 cases of hepatitis E developed during 19-month follow-up (1 in a vaccine-group participant who received 1 dose; 22 in placebo-group participants). Among the 97,356 individuals who received three doses, 15 (all in the placebo group) had confirmed hepatitis E during 12-month follow-up (vaccine efficacy, 100%).

In the 2645 participants with active surveillance for reactogenicity, local adverse events were more common in the vaccine group than in the placebo group (13.5% vs. 7.1%; P<0.0001). Serious adverse events occurred at similar rates in the two groups and were deemed unrelated to vaccination. Among the 11,165 participants studied for immunogenicity, 47.3% were HEV seropositive before vaccination. After three doses, ≥4-fold increases in antibody concentration were seen in 98.7% of vaccine-group participants vs. 2.1% of placebo-group participants (all with subclinical infection).

Comment: In this trial among adults, almost half of whom had antibody to HEV before vaccination, this recombinant vaccine was safe and highly efficacious. Future studies will need to assess duration of protection, efficacy in regions where other HEV genotypes circulate, and efficacy in groups at highest risk for severe morbidity (e.g., infants, pregnant women, individuals with chronic diseases). An editorialist speculates that the vaccine might be useful in outbreak situations.

— Mary E. Wilson, MD

Published in Journal Watch Infectious Diseases September 1, 2010