Researchers in the United States have developed adenovirus vectors that may be more effective at generating immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) than those used in the vaccines that are currently being rolled out to help combat the coronavirus disease 2019 (COVID-19) pandemic.
The researchers – from the Mayo Clinic in Rochester, Minnesota, and the University of Texas Medical Branch in Galveston also showed that the novel vectors generated stronger humoral (antibody) and cellular immune responses in rodents when vaccines were administered via the intranasal route rather than the intramuscular route.
Furthermore, the vectors generated antibodies that cross-reacted against several important mutations found in different variants of SARS-CoV-2, including the U.K. B.1.1.7 and South African B.1.351 lineages.
A pre-print version of the research paper is available on the bioRxiv* server, while the article undergoes peer review.
Currently approved vaccines “perhaps miss out on two opportunities”
Since the novel SARS-CoV-2 virus was first identified in Wuhan, China, in late December 2019, researchers have been racing to develop vaccines to combat the COVID-19 pandemic.
The unprecedented rate at which almost every vaccine technology was deployed has quickly led to the emergency use authorization and rollout of several vaccines in many countries.
However, “while many of these advanced vaccines show great promise, they perhaps miss out on two opportunities to combat SARS-CoV-2 and other mucosal pathogens,” writes Michael Barry and colleagues.
Firstly, most COVID-19 vaccines are administered intramuscularly (IM) rather than at the mucosal sites of SARS-CoV-2 entry, such as the nose.
Vaccines administered via the IM route will not generate the highest levels of mucosal protection, says the team.
Secondly, the EAU-approved vaccines are all replication-defective (RD) mRNA, DNA, or adenovirus (Ad) vaccines that do not harness the power of transgene replication to amplify antigen production and, therefore, immune responses.
Most Ad vaccines, such as those developed by Johnson & Johnson and Oxford–AstraZeneca, are RD-Ad vaccines.
The RD-Ads vaccines prevent adenovirus infections
Converting a wild replication-competent Ad (RC-Ad) to an RD-Ad is achieved by deleting a master regulator gene called E1. The RD-Ad is then unable to cause adenovirus infections.
An RD-Ad efficiently delivers viral antigen genes into host cells for translation and antigen presentation to the immune system, but the viral DNA is not replicated or amplified.
“By contrast, an E1-intact RC-Ad vector will infect a human cell and replicate an antigen gene DNA up to 10,000-fold in each infected cell,” says the team.
However, although RC-Ad vaccines have been shown to exhibit greater potency than the benchmark RD-Ad vectors, they have also been shown to cause adenovirus infections.
What did the researchers do?
Now, Barry and colleagues have developed single cycle adenovirus (SC-Ad) vectors that replicate antigen genes up to 10,000-fold in human cells but are unable to produce infectious adenovirus particles.
These SC-Ads retain E1 genes and replicate their DNA equally as well as RC-Ads, but a gene that is required for the generation of infective particles is deleted.
The researchers generated both RD-Ad and SC-Ad vectors expressing the wild-type (original) SARS-CoV-2 spike protein and compared their ability to produce this spike antigen and immune responses in rodents.
The spike protein mediates the initial step of the SARS-CoV-2 infection process by attaching to host cell receptors via its receptor-binding domain (RBD).
The team also compared the ability of mucosal intranasal (IN) and systemic intramuscular (IM) immunization to generate immune responses.
What did they find?
Barry and colleagues report that the SC-Ad vector produced 100 times more spike protein in human A549 lung cells than the RD-Ad vector.
In Syrian hamsters, both IN and IM immunization with the SC-Ad vector generated significantly stronger serum antibody responses against the spike protein than the RD-Ad vector over a 14 week period.
Furthermore, an ELISA assay revealed that the anti-spike antibodies generated by the SC-Ad vector were able to cross-react against several single point mutations in the spike RBD, including those observed in the U.K. B.1.1.7 and the South African B.1.351 variants.
The study also showed that a single immunization with the SC-Ad vector by either the IN or IM route generated significant anti-spike immunoglobulin G (IgG) antibody responses in the bronchoalveolar lavage (BAL) of mice.
However, only IN immunization generated significant anti-spike IgA responses in the BAL samples.
Furthermore, no significant increases in CD4 or CD8 T cells were observed in BAL samples following IM immunization, whereas significant increases in these cell types were observed following immunization by the IN route.
What are the implications of the study?
The researchers say the findings suggest that mucosal immunization may be of value when combatting mucosal pathogens such as SARS-CoV-2.
“This work also suggests that giving adenovirus vaccines the ability to replicate via single-cycle modifications may be of value by increasing per virus potency or by allowing more doses to be produced by using fewer virions per person,” they write.
“This could be pivotal for expanding access to vaccines for this pandemic or the next to vaccinate people in rich and poorer countries,” concludes the team.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.