40 COVID-19 vaccines and counting: Do we still need more?

There are currently 40 approved vaccines against COVID-19, of which 11 have been granted Emergency Use Authorization by the World Health Organization. [covid19.trackvaccines.org/vaccines/approved] With over 300 other candidates in the development pipeline – over 100 of which are in clinical testing [vac-lshtm.shinyapps.io/ncov_vaccine_landscape] – are new vaccines necessary?

“[N]ew vaccines that have a substantial effect on reducing mild infection and transmission are needed, even as the world attempts to learn how to live with SARS-CoV-2,” said Dr Hanna Nohynek from the Finnish Institute for Health and Welfare, Helsinki, Finland and Dr Annelies Wilder‑Smith from the University of Bern, Switzerland, in an editorial. [N Engl J Med 2022;386:2140-2142]

Apart from efficacy and safety, both experts emphasized that additional important factors include “ease of schedules, vaccine efficacy when used in routine programmes, need and frequency of boosters, cost, considerations regarding cold-chain logistics, manufacturing scalability, acceptability by communities, and scope for local or regional production.”

Other issues that need to be addressed include reduced sensitivity to currently available vaccines, waning immunity, and breakthrough infections emerging from new variants and subvariants. [Nature 2021;600:408-418; Clin Microbiol Infect 2022;28:202-221]

The idea of tailor-made vaccine shots to COVID-19 variants sounds appealing. The problem is – the world has not figured out yet what the next variant would be with some degree of confidence.

To fill the current vaccine gaps, two new vaccines produced on two different platforms* have been brought to the fore, building on the current supply constraints of COVID-19 vaccines.

 

Plant-based vaccine

CoVLP+AS03** becomes the first plant-based vaccine approved for human use, demonstrating efficacy in preventing COVID-19 caused by a spectrum of variants in unvaccinated young adults (n=24,141; median age 29 years, 51 percent male) with no history of confirmed COVID-19. [N Engl J Med 2022;386:2084-2096]

Participants were randomized 1:1 to receive two intramuscular (IM) injections of CoVLP+AS03 or placebo given 21 days apart. Only a quarter of the 165 confirmed COVID-19 cases came from the vaccine arm (efficacy of 70 percent). Against moderate-to-severe disease, efficacy was 79 percent.

CoVLP+AS03 was 100-percent protective against the Alpha, Lambda, and Mu variants. It also provided substantial protection against the Gamma (88 percent) and Delta variants (74 percent), which were the dominant variants during the trial. “However, these values probably overestimate the true variant-specific efficacy, since cases that were PCR***-positive but [negative on] sequencing were asymmetrically distributed,” the investigators noted.

The protective effect may be attributed to the strong, durable levels of neutralizing antibodies and balanced T-cell response induced by CoVLP+AS03 seen in earlier trials. [Nat Med 2021;27:1071-1078; Cell 2021;184:861-880; www.medrxiv.org/content/10.1101/2021.05.14.21257248v1]

More solicited adverse events (AEs) were reported with CoVLP+AS03 vs placebo (92 percent vs 46 percent [local] and 87 percent vs 65 percent [systemic]), but most were transient and mild to moderate. Grade 3 AE rates were low in both arms (2.1 percent vs <0.1 percent [local] and 3.1 percent vs 0.5 percent [systemic]). No COVID-19-related deaths were reported.

The efficacy of CoVLP+AS03 against the Omicron variant and as a booster shall be further evaluated.

 

RBD-dimer-based vaccine

In another trial of adults (n=28,904; median age 35 years, 68 percent male, 78.5 percent Asians), the RBD^#-dimer-based ZF2001 vaccine was effective against symptomatic and severe-to-critical COVID-19 for at least 6 months after receiving the full vaccine course (three IM injections of ZF2001 25 μg or placebo given 30 days apart). [N Engl J Med 2022;386:2097-2111]

In the updated primary efficacy analysis, 580 placebo recipients developed symptomatic COVID-19 at least 7 days after the third dose. This was nearly fourfold higher than those reported in the ZF2001 arm (n=158), yielding a vaccine efficacy of 76 percent.

“[ZF2001] met our prespecified criteria for success and exceeded the preferred criteria (≥70 percent) of WHO Target Product Profiles for COVID-19 vaccines,” said the researchers.

Six ZF2001 recipients developed severe-to-critical disease vs 43 in the placebo arm, translating to a vaccine efficacy of 88 percent. “[This suggests that] ZF2001 would provide fundamental immunity to relieve the pressure on healthcare facilities that could be overwhelmed by patients with severe-to-critical COVID-19.”

“The high cross-protection conferred by ZF2001 … against different SARS-CoV-2 variants is encouraging,” they added. Vaccine efficacy against the respective Alpha, Delta, and Kappa variants were 88, 76, and 75 percent, respectively.

Almost all AEs in the ZF2001 arm were grade 1/2, and overall serious AE rate was low (2 percent). Two ZF2001 recipients reported serious AEs that were deemed product-related in terms of hypersensitivity. “[Nonetheless,] all symptoms resolved after medical treatment without sequelae,” they continued. There were fewer COVID-19-related deaths with ZF2001 than with placebo (n=2 vs 12).

“RBD [is one of] the three major targets used in currently approved COVID-19 vaccines. It is a favourable vaccine target because it focuses the immune response on interference with RB activities,” the researchers explained. “Overall, this trial provides clinical evidence that an RBD-based vaccine is a promising alternative in the prevention of symptomatic COVID-19.”

 

Broader coverage, longer duration of protection

CoVLP+AS03 has been cleared for use in Canada, while ZF2001 has been approved in China, Colombia, Indonesia, and Uzbekistan. [covid19.trackvaccines.org/vaccines/approved]

“Both vaccines have the advantage of not requiring extreme cold-chain procedures for storage, [making] them user-friendly in primary healthcare settings [and] in low- and middle-income countries … [I]t is important that such countries were included in [these] phase III trials,” said Nohynek and Wilder‑Smith.

Additional vaccine platforms could also improve decision-making regarding vaccine selection, as certain age groups and subpopulations (eg, immunocompromised individuals, pregnant women) may require different vaccine platforms, they continued.

The more conventional format of CoVLP+AS03 may also temper the preconceived notions that some individuals have about currently available vaccines. [Annu Rev Med 2021;73:55-64; Vaccines 2021;9:900]

“The first COVID-19 vaccines used during the pandemic may not be the best long-term solution,” pointed out Nohynek and Wilder‑Smith. “The next generation of COVID-19 vaccines will need to have broader epitope coverage to provide cross-immunity against SARS-CoV-2 variants, confer a longer duration of protection, and be easy to update in a timely manner for protection against any new variants.”

“These are tall orders for vaccine developers and manufacturers, but our mandate remains to develop the best tools to prevent the emergence of new variants of concern and control the health and socioeconomic fallout from new surges,” they said.

As to when it would happen, and which technology could produce this super vaccine the fastest at scale, is the question that resonates with experts the most.