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Recombinant Subunit Vaccines

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Last reviewed: August 2, 2022

 

Overview and Mechanism

Recombinant subunit vaccines contain purified and inactivated “subunits” of the pathogens that the vaccine protects against. These subunits are chosen because of their high capability as antigens, and because the fragments are not capable of causing disease and do not involve any infectious agent, this type of vaccine is regarded to be highly safe (Tan, January 2017). Recombinant subunit vaccines are manufactured by inserting the genetic code for the subunit into other cells, such as yeast cells, that can easily grow and synthesize large amounts of the subunit needed for the vaccine. These subunits are then extracted, purified and added to the vaccine, along with other components which may include sterile saline, buffer and adjuvant.

Several different fragments of pathogens can be used as subunits for recombinant subunit vaccines. The specific fragments are chosen for their high antigenic capability and ease of manufacture. Some subunit vaccines contain pathogen fragments that are proteins; others contain pathogen fragments that are polysaccharides; and some contain polysaccharides bound (“conjugated”) to a protein for the purpose of enhancing the immune response. 

Recombinant subunit vaccines are a vaccine technology that is already being used for several other safe and effective vaccines, including recombinant hepatitis B vaccine (recombinant protein subunit), pneumococcal polysaccharide and meningococcal polysaccharide vaccines (recombinant polysaccharide subunit), and pneumococcal conjugate and meningococcal conjugate vaccines (recombinant polysaccharides conjugated to proteins). Recombinant protein subunit vaccine technology has existed for several decades; the first recombinant hepatitis B vaccine was licensed in 1986. Among the several advantages of protein subunit vaccines are that they use a well-established technology which is suitable for individuals with compromised immune systems; they are relatively stable, improving the ease of transport and storage; and they do not contain live components.

The Novavax COVID-19 vaccine (NVX-CoV2373) is the only recombinant subunit vaccine currently authorized for use in the United States by FDA. It also has a WHO Emergency Use Listing (similar to an EUA issued by FDA) for 38 other countries, including Australia, Canada, the U.K., the Republic of Korea and Denmark. NVX-CoV2373 is constructed from a recombinant, full-length wild-type SARS-CoV-2 S protein (Wuhan-Hu-1 sequence). This subunit is assembled into nanoparticles which also contain Matrix-M, a saponin-based adjuvant. The dosing schedule consists of two primary doses (5 mcg of SARS-CoV-2 recombinant spike protein with 50 mcg of Matrix-M adjuvant per dose). Primary doses are administered 3 weeks apart.

Adjuvants

Adjuvants are ingredients used in some vaccines to increase the immune response to vaccination, thereby resulting in higher levels of vaccine-induced immune protection. Adjuvants work in a variety of ways: Some prolong the viability or availability of the vaccine antigen, making sure that more vaccine antigen is available to the dendritic cells of the immune system. Others may increase the local inflammatory response by activating signals to recruit dendritic cells and monocytes to the site of the injection, and by involving T helper cell populations early in the process. Adjuvants are usually used in non-live vaccines and may be aluminum salts (aluminum potassium phosphate, aluminum hydroxyphosphate sulfate, aluminum hydroxide), oil-in-water emulsions (AS03, MF59) and virosomes, among others. Several licensed vaccines contain adjuvants, including hepatitis B vaccine, pneumococcal conjugate vaccine and some influenza vaccines.

Currently, only one vaccine authorized for use in the U.S., the Novavax COVID-19 vaccine, contains an adjuvant. The other mRNA and viral vector COVID-19 vaccines approved or authorized for U.S. use do not contain adjuvants.

The adjuvant in the Novavax recombinant subunit vaccine is called Matrix-M. Matrix-M is based on a saponin extracted from the soapbark tree (Quillaja saponaria). These saponins are formulated with cholesterol and phospholipids into nanoparticles. The adjuvant works by augmenting CD4+ T helper cell (Th1 and Th2) responses to the vaccine. Importantly, these phospholipid nanoparticles bear no immunological similarity to the lipid nanoparticles used to deliver mRNA vaccine antigens.

 


Novavax COVID-19 Vaccine

Novavax’s COVID-19 vaccine (NVX-CoV2373) is a recombinant protein subunit vaccine that is safe and effective in preventing severe COVID-19 disease. It received FDA emergency use authorization in July 2022 for use in adults ages 18 and over.

Key Novavax vaccine resources for clinicians include:

Literature

Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico (Dunkle, February 2022).

This was a Phase 3 randomized placebo-controlled trial in the U.S. and Mexico in 2021 to evaluate the efficacy and safety of NVX-CoV2373 in adults without prior history of severe SARS-CoV-2 infection. The study measured 90% effectiveness against symptomatic COVID-19 in this population.

Study population:

  • 29,949 participants were randomized between December 2020 and February 2021 (before circulation of Omicron) 2:1 to receive NVX-CoV2373 or placebo. 19,714 received NVX-CoV2373 and 9,868 received placebo. The median age was 47 years.
  • In the per-protocol study population, 48.2% were female, 75.9% were White and 47.3% reported one or more coexisting health conditions.

Key findings:

  • Among 25,452 participants in the per-protocol analysis, there were 14 cases of COVID-19 in NVX-CoV2373 recipients and 63 in placebo recipients, for a vaccine efficacy estimate of 90.4% (95% CI: 82.9% – 94.6%).
  • All cases in the NVX-CoV2373 group were mild in severity; there were 10 moderate and four severe cases in the placebo group.
  • Calculated vaccine efficacy against alpha variant was 93.6% (95% CI: 81.7% – 97.8%).
  • Local adverse events were mostly mild or moderate and occurred more frequently among NVX-CoV2373 recipients than placebo recipients after dose 1 (58% for NVX-CoV2373 vs. 21% for placebo) and dose 2 (79% for NVX-CoV2373 vs. 22% for placebo). Systemic adverse events were also mild or moderate and occurred more frequently among NVX-CoV2373 recipients than placebo recipients after dose 1 (48% vs. 40%, respectively) and dose 2 (70% vs. 36%, respectively).
  • The most frequently reported solicited adverse events were tenderness and injection-site pain (local) and headache, myalgia, fatigue and malaise (systemic).
  • No episodes of anaphylaxis, vaccine-associated enhanced COVID-19 or Guillain-Barré syndrome were identified; no statistical imbalances in myocarditis, pericarditis or vaccine-induced immunothrombosis with thrombocytopenia were observed during a short follow-up period (median: 2 months).

Limitations:

  • There was an imbalance in the number of unblinding requests by trial participants, coinciding with the introduction of other vaccines under emergency use authorization in the U.S.
  • The efficacy follow-up period was approximately 3 months, which although consistent with follow-up required for issuing emergency use authorization, is limited.
  • Vaccine efficacy was measured over a relatively shorter period during a rapidly evolving pandemic; efficacy against several variants of concern (including Delta and Omicron) was not directly assessed.

Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine (Heath, June 2022).

This was a Phase 3 randomized controlled trial of NVX-CoV2373 in 33 sites in the United Kingdom. The study measured 89.7% (95% CI: 80.2% – 94.6%) against symptomatic COVID-19 infection.

Study population:

  • A total of 14,039 participants were included in the per-protocol efficacy population. Individuals were randomized 1:1 to receive NVX-CoV2373 (n=7020) or placebo (n=7019).
  • Of the individuals in the per-protocol analysis, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses.
  • Of the participants, 48.4% were women, 94.5% were White, and the median age was 56 years.

Key findings:

  • Among 14,039 participants, 10 vaccine recipients (6.53 per 1,000 person-years) and 96 placebo recipients (63.43 per 1,000 person-years) had virologically confirmed symptomatic COVID-19 with onset at least 7 days after the second dose, for an estimated efficacy of 89.7% (95% CI: 80.2% – 94.6%).
  • Of 10 vaccine breakthrough cases, eight were caused by B.1.1.7.
  • Among participants 65 years of age and older, efficacy was estimated to be 88.9% (95% CI: 12.8% – 98.6%).
  • Among all participants, efficacy starting 14 days after the second dose was estimated to be 83.4% (95% CI: 73.6% – 89.5%).
  • A total of 2,310 participants were included in a subgroup where adverse events were solicited.
    • Local adverse events were more common in the vaccine group than placebo, both after the first dose (57.6% vs. 17.9%) and the second dose (79.6% vs. 16.4%).
  • Solicited adverse events were more common in the vaccine group than placebo, both after the first dose (45.7% vs. 36.3%) and the second dose (64.0% vs. 30.0%).
  • The most commonly reported local adverse events were injection-site tenderness or pain; the most commonly reported systemic adverse events were headache, muscle pain and fatigue.
  • Systemic adverse events were reported more often by younger vaccine recipients than older recipients (although all participants were adults) and more often after the second dose than the first dose.
    • One related serious adverse event, myocarditis, was reported in a vaccine recipient, occurring 3 days after the second dose. An independent safety monitoring board determined the event to most likely be viral myocarditis.
    • No episodes of anaphylaxis or vaccine-associated enhanced COVID-19 were reported.
    • Two deaths related to COVID-19 were reported (one in the vaccine group, one in the placebo group).
    • One instance of neuropathy meeting the Brighton Collaboration definition for Guillain-Barré syndrome was noted in the vaccine group (Dubovsky ACIP Presentation Slides, July 2022 [PDF]).

Limitations:

  • Only 5.7% of participants in this trial were non-white, leading to challenges with generalizability.
  • The efficacy estimates are derived from a relatively short observation period (median of 3 months follow-up after the second dose).
  • There is a lack of sequencing on viral isolates for cases identified in this study, although S-gene target failure has helped to identify B.1.1.7 variants.

Safety and Immunogenicity of Seven COVID-19 Vaccines as a Third Dose (Booster) Following Two Doses of ChAdOx1 nCov-19 or BNT162b2 in the U.K. (COV-BOOST): A Blinded, Multicenter, Randomized, Controlled, Phase 2 Trial (Munro, December 2021).

This was a randomized controlled trial where all participants received two doses of either ChAdOx1 or BNT162b2 (Pfizer-BioNTech) and then were subsequently randomized to receive one of seven COVID-19 vaccine types as a booster at least 70 days after the ChAdOx1 primary series or 84 days after the BNT162b2 primary series.

Study population:

  • This analysis included 96 individuals receiving a full dose of NVX-CoV2373 after ChAdOx1 primary series and 103 individuals receiving a full dose of NVX-CoV2373 after BNT162b2 primary series. All individuals were 30 years of age or older.
    • An additional 93 control individuals (for ChAdOx1) and 111 control individuals (for BNT162b2) were included. “Control” individuals received quadrivalent meningococcal conjugate vaccine.
  • The median age was 65.3 years (for individuals primed with ChAdOx1) and 62.7 (for individuals primed with BNT162b2).
  • Approximately 34.8% of NVX-Cov2373 recipients and 28.4% of control recipients primed with ChAdOx1 were health care workers.
  • Approximately 51.8% of NVX-Cov2373 recipients and 48.3% of control recipients primed with BNT162b2 were health care workers.

Key findings:

  • NVX-CoV2373 (and all other vaccines tested, including ChAdOx1, BNT162b2, mRNA-1273, Ad26, Curevac and Valneva) boosted immunity after a ChAdOx1 primary series as measured by anti-spike IgG and neutralizing assays.
  • Six vaccines (all except Valneva) boosted immunity after a BNT162b2 primary series.
  • Profiles of any grade local and systemic reactions within 7 days after all booster vaccines were similar, with fatigue and headache being the most common systemic reactions and pain being the most frequent local reaction.

Study limitations:

  • This study assesses immune response based on immunological markers, not real-world infection.
    • Although there is a relationship between increases in immune markers (such as neutralizing antibody titers) and the probability of protection given exposure, direct relationships between these metrics have not yet been officially established.
  • The interval from second to third doses in this study was shorter than the interval between the first and second doses for some individuals in this study. This is due to pandemic timelines, vaccine shortages and the need to report findings for immediate policy action. This could lead to underestimates of boosting geometric mean ratios that might be achieved at longer dose intervals.
  • Not all vaccines were able to be randomized together, which prevents direct comparison between NVX-CoV2373 and other vaccines in this study.
  • This study did not identify immunologic marker results against Alpha and Beta variants of concern.

Efficacy of NVX-Cov2373 Covid-19 Vaccine Against the B.1.351 Variant (Shinde, May 2021)

This was a Phase 2a-b trial in South Africa where adult participants 18-84 who were HIV negative and adult participants 18-64 who were HIV-positive with well-controlled disease were randomized 1:1 to receive NVX-Cov2373 or placebo. The study estimated vaccine efficacy against symptomatic COVID-19 at 49.4% (95% CI: 6.1% – 72.8%) for individuals seronegative at baseline for COVID-19.

Study population:

  • This study included 4,387 adults 18-84 who were HIV-negative and adults 18-64 who were HIV-positive with well-controlled disease.
  • A total of 2,199 individuals received at least one injection of NVX-CoV2373; 2,188 individuals received at least one injection of placebo.
  • The mean age of all participants was 32.0 years; approximately 57% of the participants were men; and 95.3% were Black African.
    • Only 4.2% of the participants in each group were between 65 and 84 years old.
  • Twenty percent of the participants were obese, 5.6% had hypertension, and 1.6% had type 2 diabetes.

Key findings:

  • Preliminary safety data were available for 889 HIV-negative participants and 80 HIV-positive participants who completed safety follow-up through at least day 35.
    • The most commonly reported local adverse event was injection site pain (37% of participants seronegative at baseline; 39% of participants seropositive in the vaccine group; 15.5% of participants in the placebo group).
    • Severe local adverse events were infrequent but occurred more often after the second dose among seronegative participants in the vaccine group, compared to the placebo group.
    • The most common systemic adverse events in vaccinated individuals were headache (20%-25%), muscle pain (17%-20%) and fatigue (12%-16%).
    • Serious adverse events were infrequent but occurred more often in the vaccine group (13 events) than the placebo group (six events). No serious adverse events were assessed by trial investigators as being related to the vaccine.
  • Symptomatic COVID-19 was observed in 15 participants in the vaccine group and 29 participants in the placebo group, corresponding to a vaccine efficacy of 49.4% (95% CI: 6.1% – 72.8%). All cases of COVID-19 in the per-protocol analysis were mild or moderate, except for one case in the placebo group.
  • Vaccine efficacy was 60.1% (95% CI: 19.9% – 80.1%) for HIV-negative individuals who were also seronegative for COVID-19 at baseline.
  • Vaccine efficacy against the B.1.351 variant specifically was 51.0% (95% CI: -0.6% – 76.2%) among HIV-negative participants and 43.0% (95% CI: -9.8% – 70.4%) in the combined HIV-negative and HIV-positive population.

Limitations:

  • The efficacy results from this trial are preliminary with a short follow-up time (median of 66 days after first dose; 45 days after second dose).

Safety

For up-to-date Novavax vaccine safety information, refer to CDC Interim Clinical Considerations for Use of COVID-19 Vaccines.

 

Dosing & Administration

For a current overview including guidance on additional doses, refer to our Vaccine Dosing & Schedule page.

 

Resources

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